CL-316243

updated

CL-316243 is a beta-3 adrenoceptor agonist research chemical with no FDA application. It raised energy expenditure and brown fat uncoupling protein and reduced carcass fat in rats, but the only human trial, 14 healthy lean men with 10 treated for 8 weeks, found no change in body weight or body composition. Insulin-mediated glucose disposal rose 45% at 4 weeks and had diminished by 8 weeks as plasma concentrations of the drug fell.

Beta-3 adrenoceptor agonist

  • An openFDA query on 9 October 2026 found no FDA application for CL-316243; mirabegron, another beta-3 agonist, was approved for overactive bladder on 28 June 2012 (MYRBETRIQ).
  • In young rats on a high-fat diet, chronic CL-316,243 raised body temperature and 24-hour energy expenditure, with three to fourfold increases in brown fat uncoupling protein and cytochrome oxidase.
  • In 14 healthy young lean men (10 treated), 8 weeks of CL 316,243 raised insulin-mediated glucose disposal 45% at 4 weeks, but the effect had diminished by 8 weeks and body weight and composition did not change.
  • A 2020 study found that human brown fat thermogenesis occurs through beta-2 receptor signaling, not beta-3.
  • A PubMed search on 9 October 2026 returned 44 records restricted to humans, and only the 1998 trial reported giving CL 316,243 to people.
  • TAK-677, another beta-3 agonist, did not change weight or abdominal fat in 65 obese adults over 29 days.

What is CL-316243, and is it approved?

CL-316243 is a beta-3 adrenoceptor agonist research chemical with no FDA application. Mirabegron, another beta-3 agonist, was approved for overactive bladder in 2012, not for fat loss.

CL-316243 is C20H18ClNNa2O7 (465.8 g/mol, CAS 138908-40-4), recorded in PubChem as the disodium salt. Doses in the literature are reported for this disodium form, and a different salt or free-acid preparation would not carry the same mass per dose. A 1995 review found it to be a selective and potent beta-3 receptor agonist.

An openFDA Drugs@FDA exact-name query for CL-316243 returned no matching application on 9 October 2026. The same database returns mirabegron, a beta-3 adrenoceptor agonist approved for overactive bladder, under MYRBETRIQ NDA 202611 approved 28 June 2012 and MYRBETRIQ GRANULES NDA 213801 approved 25 March 2021, plus generic applications from 28 September 2022 onward. The class produced an approved drug; CL-316243 is not it, and the approved one is indicated for bladder, not for fat.

PubChem CID 5312115: C20H18ClNNa2O7, 465.8 g/mol, disodium salt

Chemical identity record

National Library of Medicine. PubChem compound record CID 5312115 (CL-316243).

CL-316243: PubChem CID 5312115, C20H18ClNNa2O7, 465.8 g/mol, CAS 138908-40-4. The record is the disodium salt, disodium 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate. Doses in the literature are reported for this disodium form; a different salt or free-acid preparation would not carry the same mass per dose.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined disodium salt, no approved formulation
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
Drugs@FDA: no CL-316243 application; mirabegron (MYRBETRIQ) approved 28 June 2012 for bladder

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application records for NDA 202611 (MYRBETRIQ, mirabegron) and NDA 213801 (MYRBETRIQ GRANULES), with generic applications, and an openFDA exact-name query for CL-316243 run on 9 October 2026. Dates read from the openFDA Drugs@FDA records.

An openFDA Drugs@FDA exact-name query for CL-316243 returned no matching application on 9 October 2026. The same database returns mirabegron, a beta-3 adrenoceptor agonist approved for overactive bladder, under MYRBETRIQ NDA 202611 approved 28 June 2012 and MYRBETRIQ GRANULES NDA 213801 approved 25 March 2021, plus generic applications from 28 September 2022 onward. The class produced an approved drug; CL-316243 is not it, and the approved one is indicated for bladder, not for fat.

Participants / model
FDA application database, not a clinical population
Treatment
Exact substance-name searches
Follow-up
Query run on 9 October 2026
Study design
FDA application records and database query
Funding
not stated in the source

A US-scoped search result. The records shown are for mirabegron, the class comparator, not for CL-316243.

Read the original source
1995 review: CL 316,243 is a selective, potent beta-3 agonist; receptor pharmacology varies by species

Cell study

Pietri-Rouxel F et al. Fundam Clin Pharmacol. 1995;9(3):211-8. PMID 7557816.

A review of beta-3 adrenergic receptor pharmacology, drawing largely on stably transfected Chinese hamster ovary cells, discusses the structure and function of the receptor in various species and presents findings on ligands including CL 316,243, which was found to be a selective and potent beta-3 receptor agonist. Species-related variations in beta-3 receptor pharmacology were shown for propranolol and bupranolol.

Participants / model
Transfected Chinese hamster ovary cells and receptors from various species
Treatment
Cell culture binding and function; not a therapeutic route
Follow-up
not stated in the source
Study design
Review with original findings
Funding
not stated in the source

Cell findings. The receptor's pharmacology varies between species, which is why a rodent dose-response does not predict a human one.

Read the original source

What did the one human trial of CL-316243 find?

In 14 healthy young lean men, 8 weeks of CL 316,243 raised insulin-mediated glucose disposal by 45% at 4 weeks, but the effect had diminished by 8 weeks, and body weight and body composition did not change.

Fourteen healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat) were randomly assigned to 8 weeks of 1,500 mg per day of CL 316,243 (10 men) or placebo (4 men). It is the only study in which CL-316,243 was given to people.

After 4 weeks, insulin-mediated glucose disposal rose 45% (P<0.01) in a plasma-concentration-dependent manner (r=0.76, P<0.02), driven by an 82% increase in nonoxidative glucose disposal (P<0.01), with oxidative glucose disposal and splanchnic glucose output unchanged. The effects on insulin action were markedly diminished after 8 weeks, related to an unexpected 36% decline in plasma concentrations of the drug (P=0.08).

At 8 weeks the 24-hour respiratory quotient was lowered (P<0.001), corresponding to a 23% increase in fat oxidation (P<0.01) and a 17% decrease in carbohydrate oxidation (P=0.05). The 24-hour energy expenditure after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Glucose, insulin and leptin were unaffected, and free fatty acids rose 41% (P<0.05).

The dose is what the study gave to 10 men, not a recommendation, and it is the only human dose on record for this molecule.

Only human trial: 14 lean men, 8 weeks, insulin action up 45% at 4 weeks then faded, no fat loss

Randomized controlled trial

Weyer C et al. Diabetes. 1998;47(10):1555-61. PMID 9753292.

Fourteen healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat) were randomly assigned to 8 weeks of 1,500 mg per day of CL 316,243 (n=10) or placebo (n=4). After 4 weeks, insulin-mediated glucose disposal rose 45% (P<0.01) in a plasma-concentration-dependent manner (r=0.76, P<0.02), driven by an 82% increase in nonoxidative glucose disposal (P<0.01), with oxidative glucose disposal and splanchnic glucose output unchanged. The effects on insulin action were markedly diminished after 8 weeks, related to an unexpected 36% decline in plasma concentrations of the drug (P=0.08). At 8 weeks the 24-hour respiratory quotient was lowered (P<0.001), corresponding to a 23% increase in fat oxidation (P<0.01) and a 17% decrease in carbohydrate oxidation (P=0.05). The 24-hour energy expenditure after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Glucose, insulin and leptin were unaffected; free fatty acids rose 41% (P<0.05). There was no effect on heart rate or blood pressure and no tremors.

Participants / model
14 healthy young lean male volunteers, 10 treated and 4 on placebo
Treatment
Oral CL 316,243, 1,500 mg per day, or placebo
Follow-up
8 weeks
Study design
Randomized placebo-controlled trial
Funding
not stated in the source

The only study in which CL-316,243 was given to people. The insulin-sensitivity half of the supplier claim is supported in lean young men; the fat-loss half is not. The dose is what the study gave, not a recommendation.

Read the original source
PubMed search, 9 October 2026: 44 records, one human trial of CL 316,243

PubMed search record

PubMed search run on 9 October 2026: ("CL 316,243" OR "CL-316243" OR "CL 316243") AND humans[mh]. 44 records returned.

The search returned 44 records. The only record reporting administration of CL 316,243 to people is the 1998 trial. The remainder are rodent studies indexed under humans, isolated human tissue work such as myometrium and ureter preparations, imaging methodology, reviews, and studies of other beta-3 agonists including mirabegron. A ClinicalTrials.gov query for CL 316243 on the same day returned no studies; the 1998 trial predates the registry. In the records reviewed, one human trial of this molecule exists, with 10 people in the treated arm.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Search run on 9 October 2026
Study design
Literature search
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists.

Read the original source

Does CL-316243 activate brown fat and cut fat?

Brown fat activation and fat loss are well shown in rats. In the only human trial, insulin sensitivity improved at 4 weeks and faded by 8, and fat loss did not occur.

Sellers describe CL-316243 as activating brown fat and thermogenesis and driving fat loss, with preclinical data showing robust fat loss and improved insulin sensitivity.

The claim splits. Brown fat activation and thermogenesis are well quantified in rats, with three to fourfold increases in brown adipose uncoupling protein and cytochrome oxidase and reduced carcass fat. Improved insulin sensitivity is the part that reproduced in people, at 45% higher insulin-mediated glucose disposal at 4 weeks, and it faded by 8 weeks. Fat loss did not reproduce: the only human trial, published in 1998, found no change in body weight or body composition.

Here preclinical means rodent data, and the one human trial came back negative on the fat-loss endpoint. A PubMed search on 9 October 2026 for CL 316,243 restricted to the humans MeSH term returned 44 records, and only one reported giving CL 316,243 to people. A ClinicalTrials.gov query the same day returned no studies.

Rats on a high-fat diet: higher energy expenditure, less carcass fat, brown fat hypertrophy

Animal study

Himms-Hagen J et al. Am J Physiol. 1994;266(4 Pt 2):R1371-82. PMID 7910436.

In young rats eating a high-fat diet to induce obesity, chronic treatment with CL-316,243 increased body temperature and 24-hour energy expenditure, mainly by increasing resting metabolic rate. Food intake was not altered but carcass fat was reduced. Interscapular brown adipose tissue was markedly hypertrophied, with three to fourfold increases in the content of uncoupling protein and cytochrome oxidase. The relative frequency of the four major brown adipose cell types was not altered. White adipose tissue depots weighed less and had fewer cells by DNA content. The hypertrophy differed from that induced by endogenous norepinephrine in cold adaptation: no hyperplasia, no increase in thyroxine 5'-deiodinase activity, and no selective increase in uncoupling protein concentration.

Participants / model
Young rats on a high-fat diet
Treatment
Chronic CL-316,243; route and dose not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rat findings. The abstract states no route or dose, so no comparison with the human trial dose is possible.

Read the original source
Only human trial: 14 lean men, 8 weeks, insulin action up 45% at 4 weeks then faded, no fat loss

Randomized controlled trial

Weyer C et al. Diabetes. 1998;47(10):1555-61. PMID 9753292.

Fourteen healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat) were randomly assigned to 8 weeks of 1,500 mg per day of CL 316,243 (n=10) or placebo (n=4). After 4 weeks, insulin-mediated glucose disposal rose 45% (P<0.01) in a plasma-concentration-dependent manner (r=0.76, P<0.02), driven by an 82% increase in nonoxidative glucose disposal (P<0.01), with oxidative glucose disposal and splanchnic glucose output unchanged. The effects on insulin action were markedly diminished after 8 weeks, related to an unexpected 36% decline in plasma concentrations of the drug (P=0.08). At 8 weeks the 24-hour respiratory quotient was lowered (P<0.001), corresponding to a 23% increase in fat oxidation (P<0.01) and a 17% decrease in carbohydrate oxidation (P=0.05). The 24-hour energy expenditure after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Glucose, insulin and leptin were unaffected; free fatty acids rose 41% (P<0.05). There was no effect on heart rate or blood pressure and no tremors.

Participants / model
14 healthy young lean male volunteers, 10 treated and 4 on placebo
Treatment
Oral CL 316,243, 1,500 mg per day, or placebo
Follow-up
8 weeks
Study design
Randomized placebo-controlled trial
Funding
not stated in the source

The only study in which CL-316,243 was given to people. The insulin-sensitivity half of the supplier claim is supported in lean young men; the fat-loss half is not. The dose is what the study gave, not a recommendation.

Read the original source
PubMed search, 9 October 2026: 44 records, one human trial of CL 316,243

PubMed search record

PubMed search run on 9 October 2026: ("CL 316,243" OR "CL-316243" OR "CL 316243") AND humans[mh]. 44 records returned.

The search returned 44 records. The only record reporting administration of CL 316,243 to people is the 1998 trial. The remainder are rodent studies indexed under humans, isolated human tissue work such as myometrium and ureter preparations, imaging methodology, reviews, and studies of other beta-3 agonists including mirabegron. A ClinicalTrials.gov query for CL 316243 on the same day returned no studies; the 1998 trial predates the registry. In the records reviewed, one human trial of this molecule exists, with 10 people in the treated arm.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Search run on 9 October 2026
Study design
Literature search
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists.

Read the original source

What did the rodent studies find?

In young rats on a high-fat diet, chronic CL-316,243 raised body temperature, energy expenditure and brown fat uncoupling protein and reduced carcass fat. In mice, the glucose-lowering effect faded with repeated treatment while the energy expenditure effect did not.

In young rats eating a high-fat diet, chronic treatment with CL-316,243 increased body temperature and 24-hour energy expenditure, mainly by increasing resting metabolic rate. Food intake was not altered but carcass fat was reduced. Interscapular brown adipose tissue was markedly hypertrophied, with three to fourfold increases in the content of uncoupling protein and cytochrome oxidase, and white adipose tissue depots weighed less and had fewer cells by DNA content. The hypertrophy differed from that induced by endogenous norepinephrine in cold adaptation: no hyperplasia, no increase in thyroxine 5'-deiodinase activity, and no selective increase in uncoupling protein concentration.

In mice under thermoneutral housing, the acute effects of CL 316,243 to increase serum fatty acids and insulin and reduce blood glucose, but not the increase in energy expenditure, were attenuated after repeated treatment, in parallel with reduced protein kinase A signaling in white adipose tissue. The attenuation was confirmed in high-fat fed mice and in UCP1 knockout mice, and was rescued by the phosphodiesterase inhibitor cilostamide. The glucose-lowering effect fades with repeated use; the thermogenic effect did not in this model.

Neither abstract states the route or dose, so no comparison with the human trial dose is drawn here.

Rats on a high-fat diet: higher energy expenditure, less carcass fat, brown fat hypertrophy

Animal study

Himms-Hagen J et al. Am J Physiol. 1994;266(4 Pt 2):R1371-82. PMID 7910436.

In young rats eating a high-fat diet to induce obesity, chronic treatment with CL-316,243 increased body temperature and 24-hour energy expenditure, mainly by increasing resting metabolic rate. Food intake was not altered but carcass fat was reduced. Interscapular brown adipose tissue was markedly hypertrophied, with three to fourfold increases in the content of uncoupling protein and cytochrome oxidase. The relative frequency of the four major brown adipose cell types was not altered. White adipose tissue depots weighed less and had fewer cells by DNA content. The hypertrophy differed from that induced by endogenous norepinephrine in cold adaptation: no hyperplasia, no increase in thyroxine 5'-deiodinase activity, and no selective increase in uncoupling protein concentration.

Participants / model
Young rats on a high-fat diet
Treatment
Chronic CL-316,243; route and dose not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rat findings. The abstract states no route or dose, so no comparison with the human trial dose is possible.

Read the original source
Mice: glucose-lowering effect fades with repeated treatment, thermogenic effect did not

Animal study

Medak KD et al. Physiol Rep. 2022;10(4):e15187. PMID 35179321.

Repeated activation of the beta-3 receptor with CL 316,243 remodels white adipose tissue with increased mitochondrial enzymes and UCP1 expression, but the acute effects had been studied mostly in treatment-naive animals at room temperature. Under thermoneutral housing, the acute effects of CL to increase serum fatty acids and insulin and reduce blood glucose, but not the increase in energy expenditure, were attenuated in mice after repeated treatment, in parallel with reduced indices of protein kinase A signaling in white adipose tissue including phosphorylation of hormone sensitive lipase. The attenuation was confirmed in high-fat fed mice and in UCP1 knockout mice, and was rescued by the phosphodiesterase inhibitor cilostamide.

Participants / model
Mice, including high-fat fed and UCP1 knockout, under thermoneutral housing
Treatment
Repeated CL 316,243 treatment, with and without cilostamide; route and dose not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Mouse findings. The glucose-lowering effect fades with repeated use; the thermogenic effect did not in this model.

Read the original source

Why did the rodent results not carry over to people?

A 2020 study found that human brown fat thermogenesis runs through the beta-2 receptor, not beta-3. The beta-3 receptor also differs between species, and other beta-3 agonists such as mirabegron and TAK-677 did little for weight or fat in people.

A 2020 study reports that, in contrast to rodents, human brown adipose tissue thermogenesis is not mediated by beta-3 receptor stimulation. ADRB2 was co-expressed with UCP1 in human brown adipocytes, and receptor stimulation and inhibition plus knockdown of ADRB1, ADRB2 and ADRB3 confirmed that brown adipose lipolysis and thermogenesis occur through beta-2 receptor signaling in humans. Oral mirabegron raised brown adipose thermogenesis only at the maximal allowable dose, through off-target beta-1 and beta-2 binding with increased cardiovascular responses and white adipose lipolysis. This is mirabegron, not CL-316,243.

A 1995 review of beta-3 receptor pharmacology, drawing largely on transfected Chinese hamster ovary cells, showed species-related variations in the receptor's pharmacology for propranolol and bupranolol. A 2008 review states that beta-3 agonists have not become drugs for obesity or diabetes, that some also stimulate other beta receptors in humans, and that studies on this receptor show the difficulty of predicting in vivo effects of agonist drugs from in vitro data.

Two other beta-3 agonists show the same pattern in people. A meta-analysis of 6 mirabegron studies found no significant change in brown adipose tissue volume (p=0.72) or blood glucose (p=0.52), with increases in brown fat activity, body temperature, resting energy expenditure, heart rate and diastolic blood pressure (all p<0.01). In 65 obese adults given TAK-677 for 29 days, weight, fat-free mass and abdominal fat depots did not differ from placebo, although 24-hour energy expenditure rose slightly at the higher dose (13 +/- 17 versus -39 +/- 18 kcal per day, P<0.05). Neither is CL-316,243.

Mirabegron study (different compound): human brown fat thermogenesis runs through beta-2, not beta-3

Human study

Blondin DP et al. Cell Metab. 2020;32(2):287-300.e7. PMID 32755608.

Pharmacological stimulations targeting the beta-3 adrenergic receptor, the receptor believed to mediate brown adipose tissue thermogenesis, have historically performed poorly in human clinical trials. The authors report that, in contrast to rodents, human brown adipose tissue thermogenesis is not mediated by stimulation of the beta-3 receptor. Oral mirabegron only elicited increases in brown adipose thermogenesis when ingested at the maximal allowable dose, which led to off-target binding to the beta-1 and beta-2 receptors and thereby increased cardiovascular responses and white adipose lipolysis. ADRB2 was co-expressed with UCP1 in human brown adipocytes, and pharmacological stimulation and inhibition of the beta-2 receptor plus knockdown of ADRB1, ADRB2 and ADRB3 in human brown adipocytes all confirmed that brown adipose lipolysis and thermogenesis occur through beta-2 receptor signaling in humans.

Participants / model
Human participants and human brown adipocytes
Treatment
Oral mirabegron in humans; receptor agonists, antagonists and knockdown in human brown adipocytes
Follow-up
not stated in the source
Study design
Original human and cell study
Funding
not stated in the source

This is mirabegron, not CL-316,243. It explains why rodent beta-3 results did not carry over.

Read the original source
1995 review: CL 316,243 is a selective, potent beta-3 agonist; receptor pharmacology varies by species

Cell study

Pietri-Rouxel F et al. Fundam Clin Pharmacol. 1995;9(3):211-8. PMID 7557816.

A review of beta-3 adrenergic receptor pharmacology, drawing largely on stably transfected Chinese hamster ovary cells, discusses the structure and function of the receptor in various species and presents findings on ligands including CL 316,243, which was found to be a selective and potent beta-3 receptor agonist. Species-related variations in beta-3 receptor pharmacology were shown for propranolol and bupranolol.

Participants / model
Transfected Chinese hamster ovary cells and receptors from various species
Treatment
Cell culture binding and function; not a therapeutic route
Follow-up
not stated in the source
Study design
Review with original findings
Funding
not stated in the source

Cell findings. The receptor's pharmacology varies between species, which is why a rodent dose-response does not predict a human one.

Read the original source
2008 review: beta-3 agonists did not become obesity or diabetes drugs

Human study

Arch JR. Naunyn Schmiedebergs Arch Pharmacol. 2008;378(2):225-40. PMID 18612674.

A review states that although beta-3 adrenoceptor agonists have not become drugs for the treatment of obesity or diabetes, they offer perspectives on obesity drug discovery. Some beta-3 agonists also stimulate other beta receptors in humans. The author notes that the beta-3 receptor can display variable pharmacologies of its own depending on the radioligand used in binding studies or the functional response measured, and that studies on this receptor demonstrate the difficulty of predicting the in vivo effects of agonist drugs from in vitro data.

Participants / model
Published beta-3 agonist programs, not a population
Treatment
Not applicable
Follow-up
not stated in the source
Study design
Narrative review
Funding
not stated in the source

A summary of development history and receptor pharmacology, not a primary study.

Read the original source
Mirabegron meta-analysis (different compound): 6 studies, brown fat volume and glucose unchanged

Systematic review and meta-analysis

Ma L et al. Eur J Clin Pharmacol. 2024;80(3):317-333. PMID 38159219.

A systematic review and meta-analysis searched four databases to March 2023, reviewed 10 papers and included 6 in the meta-analysis. There were no significant changes in brown adipose tissue volume (p=0.72) or blood glucose (p=0.52) with mirabegron compared with placebo or pre-dose. The abstract reports increases in brown adipose tissue activity (p<0.01), blood non-esterified fatty acids (p<0.01), body temperature (p<0.01), resting energy expenditure (p<0.01), heart rate (p<0.01), diastolic blood pressure (p<0.01) and blood insulin (p<0.01).

Participants / model
Participants across 6 studies pooled in meta-analysis
Treatment
Oral mirabegron
Follow-up
Studies searched to March 2023
Study design
Systematic review and meta-analysis
Funding
not stated in the source

This is mirabegron, not CL-316,243. The abstract's systolic blood pressure entry is listed with the increases but carries p=0.25, so it is not quoted.

Read the original source
TAK-677 trial (different compound): 65 obese adults, 29 days, no weight or fat change

Randomized controlled trial

Redman LM et al. J Clin Endocrinol Metab. 2007;92(2):527-31. PMID 17118998.

Sixty-five obese men and women (BMI 33.9 +/- 2.1 kg/m2, age 31.4 +/- 0.9 years) were randomized to TAK-677 0.1 mg twice daily (n=21), 0.5 mg twice daily (n=22) or placebo twice daily (n=22) for 29 days. The drug was well tolerated, but heart rate was elevated by 9 +/- 2 beats per minute at the 0.5 mg twice-daily dose. After 28 days there was no change in 24-hour respiratory quotient at either dose (P=0.1 and P=1.0). The 0.5 mg twice-daily dose produced a small increase in 24-hour energy expenditure versus placebo, a change from baseline of 13 +/- 17 versus -39 +/- 18 kcal per day (P<0.05). Changes in weight, fat-free mass and visceral or subcutaneous abdominal fat depots did not differ between the three groups, nor did fasting insulin, free fatty acid or glucose. The acute studies showed large interindividual variability in plasma concentrations, which the authors say indicates possible problems with bioavailability and therefore efficacy.

Participants / model
65 obese men and women
Treatment
Oral TAK-677, 0.1 or 0.5 mg twice daily, or placebo
Follow-up
29 days
Study design
Randomized placebo-controlled trial
Funding
not stated in the source

This is TAK-677, a different beta-3 agonist, not CL-316,243.

Read the original source

How does CL-316243 work, and what does the body do with it?

CL-316243 is a selective, potent beta-3 receptor agonist. In rats it raised resting metabolic rate and brown fat uncoupling protein, and in the human trial plasma concentrations of the drug fell 36% over 8 weeks while its insulin effect faded.

In a 1995 review, CL 316,243 was found to be a selective and potent beta-3 receptor agonist. In young rats on a high-fat diet, chronic treatment increased body temperature and 24-hour energy expenditure, mainly by increasing resting metabolic rate, with three to fourfold increases in brown adipose uncoupling protein and cytochrome oxidase.

In the human trial, the 24-hour respiratory quotient fell and fat oxidation rose 23% at 8 weeks, but 24-hour energy expenditure did not differ from baseline and body weight and composition did not change.

Plasma concentrations of the drug declined 36% in the trial (P=0.08), and the effects on insulin action diminished in parallel. The sources reviewed give no half-life, Tmax or bioavailability figure. Doses in the literature are for the disodium salt, so another salt or free acid would not carry the same mass per dose.

1995 review: CL 316,243 is a selective, potent beta-3 agonist; receptor pharmacology varies by species

Cell study

Pietri-Rouxel F et al. Fundam Clin Pharmacol. 1995;9(3):211-8. PMID 7557816.

A review of beta-3 adrenergic receptor pharmacology, drawing largely on stably transfected Chinese hamster ovary cells, discusses the structure and function of the receptor in various species and presents findings on ligands including CL 316,243, which was found to be a selective and potent beta-3 receptor agonist. Species-related variations in beta-3 receptor pharmacology were shown for propranolol and bupranolol.

Participants / model
Transfected Chinese hamster ovary cells and receptors from various species
Treatment
Cell culture binding and function; not a therapeutic route
Follow-up
not stated in the source
Study design
Review with original findings
Funding
not stated in the source

Cell findings. The receptor's pharmacology varies between species, which is why a rodent dose-response does not predict a human one.

Read the original source
Rats on a high-fat diet: higher energy expenditure, less carcass fat, brown fat hypertrophy

Animal study

Himms-Hagen J et al. Am J Physiol. 1994;266(4 Pt 2):R1371-82. PMID 7910436.

In young rats eating a high-fat diet to induce obesity, chronic treatment with CL-316,243 increased body temperature and 24-hour energy expenditure, mainly by increasing resting metabolic rate. Food intake was not altered but carcass fat was reduced. Interscapular brown adipose tissue was markedly hypertrophied, with three to fourfold increases in the content of uncoupling protein and cytochrome oxidase. The relative frequency of the four major brown adipose cell types was not altered. White adipose tissue depots weighed less and had fewer cells by DNA content. The hypertrophy differed from that induced by endogenous norepinephrine in cold adaptation: no hyperplasia, no increase in thyroxine 5'-deiodinase activity, and no selective increase in uncoupling protein concentration.

Participants / model
Young rats on a high-fat diet
Treatment
Chronic CL-316,243; route and dose not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rat findings. The abstract states no route or dose, so no comparison with the human trial dose is possible.

Read the original source
Only human trial: 14 lean men, 8 weeks, insulin action up 45% at 4 weeks then faded, no fat loss

Randomized controlled trial

Weyer C et al. Diabetes. 1998;47(10):1555-61. PMID 9753292.

Fourteen healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat) were randomly assigned to 8 weeks of 1,500 mg per day of CL 316,243 (n=10) or placebo (n=4). After 4 weeks, insulin-mediated glucose disposal rose 45% (P<0.01) in a plasma-concentration-dependent manner (r=0.76, P<0.02), driven by an 82% increase in nonoxidative glucose disposal (P<0.01), with oxidative glucose disposal and splanchnic glucose output unchanged. The effects on insulin action were markedly diminished after 8 weeks, related to an unexpected 36% decline in plasma concentrations of the drug (P=0.08). At 8 weeks the 24-hour respiratory quotient was lowered (P<0.001), corresponding to a 23% increase in fat oxidation (P<0.01) and a 17% decrease in carbohydrate oxidation (P=0.05). The 24-hour energy expenditure after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Glucose, insulin and leptin were unaffected; free fatty acids rose 41% (P<0.05). There was no effect on heart rate or blood pressure and no tremors.

Participants / model
14 healthy young lean male volunteers, 10 treated and 4 on placebo
Treatment
Oral CL 316,243, 1,500 mg per day, or placebo
Follow-up
8 weeks
Study design
Randomized placebo-controlled trial
Funding
not stated in the source

The only study in which CL-316,243 was given to people. The insulin-sensitivity half of the supplier claim is supported in lean young men; the fat-loss half is not. The dose is what the study gave, not a recommendation.

Read the original source
PubChem CID 5312115: C20H18ClNNa2O7, 465.8 g/mol, disodium salt

Chemical identity record

National Library of Medicine. PubChem compound record CID 5312115 (CL-316243).

CL-316243: PubChem CID 5312115, C20H18ClNNa2O7, 465.8 g/mol, CAS 138908-40-4. The record is the disodium salt, disodium 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate. Doses in the literature are reported for this disodium form; a different salt or free-acid preparation would not carry the same mass per dose.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined disodium salt, no approved formulation
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source

What risks did the human and animal studies report?

In the 14-man trial there was no effect on heart rate or blood pressure and no tremors, but only 10 men received the drug and the sources reviewed report no other safety outcomes. Other beta-3 agonists raised heart rate.

In the 14-man trial there was no effect on heart rate or blood pressure and no tremors. Only 10 men received the drug, the trial lasted 8 weeks, and free fatty acids rose 41% (P<0.05). The sources reviewed report no other safety outcomes for CL-316,243 in people.

Other beta-3 agonists raised heart rate. In the mirabegron meta-analysis, heart rate and diastolic blood pressure rose (both p<0.01), and in the TAK-677 trial heart rate was elevated by 9 +/- 2 beats per minute at the 0.5 mg twice-daily dose. The 2020 study reports that mirabegron at the maximal allowable dose bound beta-1 and beta-2 receptors and increased cardiovascular responses and white adipose lipolysis. These are other molecules, not CL-316,243.

Only human trial: 14 lean men, 8 weeks, insulin action up 45% at 4 weeks then faded, no fat loss

Randomized controlled trial

Weyer C et al. Diabetes. 1998;47(10):1555-61. PMID 9753292.

Fourteen healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat) were randomly assigned to 8 weeks of 1,500 mg per day of CL 316,243 (n=10) or placebo (n=4). After 4 weeks, insulin-mediated glucose disposal rose 45% (P<0.01) in a plasma-concentration-dependent manner (r=0.76, P<0.02), driven by an 82% increase in nonoxidative glucose disposal (P<0.01), with oxidative glucose disposal and splanchnic glucose output unchanged. The effects on insulin action were markedly diminished after 8 weeks, related to an unexpected 36% decline in plasma concentrations of the drug (P=0.08). At 8 weeks the 24-hour respiratory quotient was lowered (P<0.001), corresponding to a 23% increase in fat oxidation (P<0.01) and a 17% decrease in carbohydrate oxidation (P=0.05). The 24-hour energy expenditure after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Glucose, insulin and leptin were unaffected; free fatty acids rose 41% (P<0.05). There was no effect on heart rate or blood pressure and no tremors.

Participants / model
14 healthy young lean male volunteers, 10 treated and 4 on placebo
Treatment
Oral CL 316,243, 1,500 mg per day, or placebo
Follow-up
8 weeks
Study design
Randomized placebo-controlled trial
Funding
not stated in the source

The only study in which CL-316,243 was given to people. The insulin-sensitivity half of the supplier claim is supported in lean young men; the fat-loss half is not. The dose is what the study gave, not a recommendation.

Read the original source
Mirabegron meta-analysis (different compound): 6 studies, brown fat volume and glucose unchanged

Systematic review and meta-analysis

Ma L et al. Eur J Clin Pharmacol. 2024;80(3):317-333. PMID 38159219.

A systematic review and meta-analysis searched four databases to March 2023, reviewed 10 papers and included 6 in the meta-analysis. There were no significant changes in brown adipose tissue volume (p=0.72) or blood glucose (p=0.52) with mirabegron compared with placebo or pre-dose. The abstract reports increases in brown adipose tissue activity (p<0.01), blood non-esterified fatty acids (p<0.01), body temperature (p<0.01), resting energy expenditure (p<0.01), heart rate (p<0.01), diastolic blood pressure (p<0.01) and blood insulin (p<0.01).

Participants / model
Participants across 6 studies pooled in meta-analysis
Treatment
Oral mirabegron
Follow-up
Studies searched to March 2023
Study design
Systematic review and meta-analysis
Funding
not stated in the source

This is mirabegron, not CL-316,243. The abstract's systolic blood pressure entry is listed with the increases but carries p=0.25, so it is not quoted.

Read the original source
TAK-677 trial (different compound): 65 obese adults, 29 days, no weight or fat change

Randomized controlled trial

Redman LM et al. J Clin Endocrinol Metab. 2007;92(2):527-31. PMID 17118998.

Sixty-five obese men and women (BMI 33.9 +/- 2.1 kg/m2, age 31.4 +/- 0.9 years) were randomized to TAK-677 0.1 mg twice daily (n=21), 0.5 mg twice daily (n=22) or placebo twice daily (n=22) for 29 days. The drug was well tolerated, but heart rate was elevated by 9 +/- 2 beats per minute at the 0.5 mg twice-daily dose. After 28 days there was no change in 24-hour respiratory quotient at either dose (P=0.1 and P=1.0). The 0.5 mg twice-daily dose produced a small increase in 24-hour energy expenditure versus placebo, a change from baseline of 13 +/- 17 versus -39 +/- 18 kcal per day (P<0.05). Changes in weight, fat-free mass and visceral or subcutaneous abdominal fat depots did not differ between the three groups, nor did fasting insulin, free fatty acid or glucose. The acute studies showed large interindividual variability in plasma concentrations, which the authors say indicates possible problems with bioavailability and therefore efficacy.

Participants / model
65 obese men and women
Treatment
Oral TAK-677, 0.1 or 0.5 mg twice daily, or placebo
Follow-up
29 days
Study design
Randomized placebo-controlled trial
Funding
not stated in the source

This is TAK-677, a different beta-3 agonist, not CL-316,243.

Read the original source
Mirabegron study (different compound): human brown fat thermogenesis runs through beta-2, not beta-3

Human study

Blondin DP et al. Cell Metab. 2020;32(2):287-300.e7. PMID 32755608.

Pharmacological stimulations targeting the beta-3 adrenergic receptor, the receptor believed to mediate brown adipose tissue thermogenesis, have historically performed poorly in human clinical trials. The authors report that, in contrast to rodents, human brown adipose tissue thermogenesis is not mediated by stimulation of the beta-3 receptor. Oral mirabegron only elicited increases in brown adipose thermogenesis when ingested at the maximal allowable dose, which led to off-target binding to the beta-1 and beta-2 receptors and thereby increased cardiovascular responses and white adipose lipolysis. ADRB2 was co-expressed with UCP1 in human brown adipocytes, and pharmacological stimulation and inhibition of the beta-2 receptor plus knockdown of ADRB1, ADRB2 and ADRB3 in human brown adipocytes all confirmed that brown adipose lipolysis and thermogenesis occur through beta-2 receptor signaling in humans.

Participants / model
Human participants and human brown adipocytes
Treatment
Oral mirabegron in humans; receptor agonists, antagonists and knockdown in human brown adipocytes
Follow-up
not stated in the source
Study design
Original human and cell study
Funding
not stated in the source

This is mirabegron, not CL-316,243. It explains why rodent beta-3 results did not carry over.

Read the original source

Why does CL-316243 sit in D tier?

One human trial with 10 treated men found no change in body weight or composition after 8 weeks, and the reason is known: human brown fat thermogenesis runs through the beta-2 receptor, not beta-3. Insulin sensitivity improved at 4 weeks and faded by 8.

One human trial exists, it had 10 people in the treated arm, and it found no change in body weight or body composition after 8 weeks. The reason is documented: human brown fat thermogenesis runs through the beta-2 receptor, not beta-3, which was shown in people and in human brown adipocytes in 2020, and the beta-3 receptor's pharmacology varies between species. Plasma concentrations of the drug fell 36% over the trial, and the effects on insulin action tracked that decline.

The supplier claim splits. Brown fat activation and thermogenesis are real in rats, and improved insulin sensitivity reproduced in people at 4 weeks before fading. Fat loss did not reproduce, so the claim of robust preclinical fat loss holds only if preclinical is read as rodent data.

Only human trial: 14 lean men, 8 weeks, insulin action up 45% at 4 weeks then faded, no fat loss

Randomized controlled trial

Weyer C et al. Diabetes. 1998;47(10):1555-61. PMID 9753292.

Fourteen healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat) were randomly assigned to 8 weeks of 1,500 mg per day of CL 316,243 (n=10) or placebo (n=4). After 4 weeks, insulin-mediated glucose disposal rose 45% (P<0.01) in a plasma-concentration-dependent manner (r=0.76, P<0.02), driven by an 82% increase in nonoxidative glucose disposal (P<0.01), with oxidative glucose disposal and splanchnic glucose output unchanged. The effects on insulin action were markedly diminished after 8 weeks, related to an unexpected 36% decline in plasma concentrations of the drug (P=0.08). At 8 weeks the 24-hour respiratory quotient was lowered (P<0.001), corresponding to a 23% increase in fat oxidation (P<0.01) and a 17% decrease in carbohydrate oxidation (P=0.05). The 24-hour energy expenditure after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Glucose, insulin and leptin were unaffected; free fatty acids rose 41% (P<0.05). There was no effect on heart rate or blood pressure and no tremors.

Participants / model
14 healthy young lean male volunteers, 10 treated and 4 on placebo
Treatment
Oral CL 316,243, 1,500 mg per day, or placebo
Follow-up
8 weeks
Study design
Randomized placebo-controlled trial
Funding
not stated in the source

The only study in which CL-316,243 was given to people. The insulin-sensitivity half of the supplier claim is supported in lean young men; the fat-loss half is not. The dose is what the study gave, not a recommendation.

Read the original source
Mirabegron study (different compound): human brown fat thermogenesis runs through beta-2, not beta-3

Human study

Blondin DP et al. Cell Metab. 2020;32(2):287-300.e7. PMID 32755608.

Pharmacological stimulations targeting the beta-3 adrenergic receptor, the receptor believed to mediate brown adipose tissue thermogenesis, have historically performed poorly in human clinical trials. The authors report that, in contrast to rodents, human brown adipose tissue thermogenesis is not mediated by stimulation of the beta-3 receptor. Oral mirabegron only elicited increases in brown adipose thermogenesis when ingested at the maximal allowable dose, which led to off-target binding to the beta-1 and beta-2 receptors and thereby increased cardiovascular responses and white adipose lipolysis. ADRB2 was co-expressed with UCP1 in human brown adipocytes, and pharmacological stimulation and inhibition of the beta-2 receptor plus knockdown of ADRB1, ADRB2 and ADRB3 in human brown adipocytes all confirmed that brown adipose lipolysis and thermogenesis occur through beta-2 receptor signaling in humans.

Participants / model
Human participants and human brown adipocytes
Treatment
Oral mirabegron in humans; receptor agonists, antagonists and knockdown in human brown adipocytes
Follow-up
not stated in the source
Study design
Original human and cell study
Funding
not stated in the source

This is mirabegron, not CL-316,243. It explains why rodent beta-3 results did not carry over.

Read the original source
1995 review: CL 316,243 is a selective, potent beta-3 agonist; receptor pharmacology varies by species

Cell study

Pietri-Rouxel F et al. Fundam Clin Pharmacol. 1995;9(3):211-8. PMID 7557816.

A review of beta-3 adrenergic receptor pharmacology, drawing largely on stably transfected Chinese hamster ovary cells, discusses the structure and function of the receptor in various species and presents findings on ligands including CL 316,243, which was found to be a selective and potent beta-3 receptor agonist. Species-related variations in beta-3 receptor pharmacology were shown for propranolol and bupranolol.

Participants / model
Transfected Chinese hamster ovary cells and receptors from various species
Treatment
Cell culture binding and function; not a therapeutic route
Follow-up
not stated in the source
Study design
Review with original findings
Funding
not stated in the source

Cell findings. The receptor's pharmacology varies between species, which is why a rodent dose-response does not predict a human one.

Read the original source
Rats on a high-fat diet: higher energy expenditure, less carcass fat, brown fat hypertrophy

Animal study

Himms-Hagen J et al. Am J Physiol. 1994;266(4 Pt 2):R1371-82. PMID 7910436.

In young rats eating a high-fat diet to induce obesity, chronic treatment with CL-316,243 increased body temperature and 24-hour energy expenditure, mainly by increasing resting metabolic rate. Food intake was not altered but carcass fat was reduced. Interscapular brown adipose tissue was markedly hypertrophied, with three to fourfold increases in the content of uncoupling protein and cytochrome oxidase. The relative frequency of the four major brown adipose cell types was not altered. White adipose tissue depots weighed less and had fewer cells by DNA content. The hypertrophy differed from that induced by endogenous norepinephrine in cold adaptation: no hyperplasia, no increase in thyroxine 5'-deiodinase activity, and no selective increase in uncoupling protein concentration.

Participants / model
Young rats on a high-fat diet
Treatment
Chronic CL-316,243; route and dose not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rat findings. The abstract states no route or dose, so no comparison with the human trial dose is possible.

Read the original source

Studies and sources

PubChem CID 5312115: C20H18ClNNa2O7, 465.8 g/mol, disodium salt

Chemical identity record

National Library of Medicine. PubChem compound record CID 5312115 (CL-316243).

CL-316243: PubChem CID 5312115, C20H18ClNNa2O7, 465.8 g/mol, CAS 138908-40-4. The record is the disodium salt, disodium 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate. Doses in the literature are reported for this disodium form; a different salt or free-acid preparation would not carry the same mass per dose.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined disodium salt, no approved formulation
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
Drugs@FDA: no CL-316243 application; mirabegron (MYRBETRIQ) approved 28 June 2012 for bladder

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application records for NDA 202611 (MYRBETRIQ, mirabegron) and NDA 213801 (MYRBETRIQ GRANULES), with generic applications, and an openFDA exact-name query for CL-316243 run on 9 October 2026. Dates read from the openFDA Drugs@FDA records.

An openFDA Drugs@FDA exact-name query for CL-316243 returned no matching application on 9 October 2026. The same database returns mirabegron, a beta-3 adrenoceptor agonist approved for overactive bladder, under MYRBETRIQ NDA 202611 approved 28 June 2012 and MYRBETRIQ GRANULES NDA 213801 approved 25 March 2021, plus generic applications from 28 September 2022 onward. The class produced an approved drug; CL-316243 is not it, and the approved one is indicated for bladder, not for fat.

Participants / model
FDA application database, not a clinical population
Treatment
Exact substance-name searches
Follow-up
Query run on 9 October 2026
Study design
FDA application records and database query
Funding
not stated in the source

A US-scoped search result. The records shown are for mirabegron, the class comparator, not for CL-316243.

Read the original source
Rats on a high-fat diet: higher energy expenditure, less carcass fat, brown fat hypertrophy

Animal study

Himms-Hagen J et al. Am J Physiol. 1994;266(4 Pt 2):R1371-82. PMID 7910436.

In young rats eating a high-fat diet to induce obesity, chronic treatment with CL-316,243 increased body temperature and 24-hour energy expenditure, mainly by increasing resting metabolic rate. Food intake was not altered but carcass fat was reduced. Interscapular brown adipose tissue was markedly hypertrophied, with three to fourfold increases in the content of uncoupling protein and cytochrome oxidase. The relative frequency of the four major brown adipose cell types was not altered. White adipose tissue depots weighed less and had fewer cells by DNA content. The hypertrophy differed from that induced by endogenous norepinephrine in cold adaptation: no hyperplasia, no increase in thyroxine 5'-deiodinase activity, and no selective increase in uncoupling protein concentration.

Participants / model
Young rats on a high-fat diet
Treatment
Chronic CL-316,243; route and dose not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rat findings. The abstract states no route or dose, so no comparison with the human trial dose is possible.

Read the original source
Only human trial: 14 lean men, 8 weeks, insulin action up 45% at 4 weeks then faded, no fat loss

Randomized controlled trial

Weyer C et al. Diabetes. 1998;47(10):1555-61. PMID 9753292.

Fourteen healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat) were randomly assigned to 8 weeks of 1,500 mg per day of CL 316,243 (n=10) or placebo (n=4). After 4 weeks, insulin-mediated glucose disposal rose 45% (P<0.01) in a plasma-concentration-dependent manner (r=0.76, P<0.02), driven by an 82% increase in nonoxidative glucose disposal (P<0.01), with oxidative glucose disposal and splanchnic glucose output unchanged. The effects on insulin action were markedly diminished after 8 weeks, related to an unexpected 36% decline in plasma concentrations of the drug (P=0.08). At 8 weeks the 24-hour respiratory quotient was lowered (P<0.001), corresponding to a 23% increase in fat oxidation (P<0.01) and a 17% decrease in carbohydrate oxidation (P=0.05). The 24-hour energy expenditure after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Glucose, insulin and leptin were unaffected; free fatty acids rose 41% (P<0.05). There was no effect on heart rate or blood pressure and no tremors.

Participants / model
14 healthy young lean male volunteers, 10 treated and 4 on placebo
Treatment
Oral CL 316,243, 1,500 mg per day, or placebo
Follow-up
8 weeks
Study design
Randomized placebo-controlled trial
Funding
not stated in the source

The only study in which CL-316,243 was given to people. The insulin-sensitivity half of the supplier claim is supported in lean young men; the fat-loss half is not. The dose is what the study gave, not a recommendation.

Read the original source
Mirabegron study (different compound): human brown fat thermogenesis runs through beta-2, not beta-3

Human study

Blondin DP et al. Cell Metab. 2020;32(2):287-300.e7. PMID 32755608.

Pharmacological stimulations targeting the beta-3 adrenergic receptor, the receptor believed to mediate brown adipose tissue thermogenesis, have historically performed poorly in human clinical trials. The authors report that, in contrast to rodents, human brown adipose tissue thermogenesis is not mediated by stimulation of the beta-3 receptor. Oral mirabegron only elicited increases in brown adipose thermogenesis when ingested at the maximal allowable dose, which led to off-target binding to the beta-1 and beta-2 receptors and thereby increased cardiovascular responses and white adipose lipolysis. ADRB2 was co-expressed with UCP1 in human brown adipocytes, and pharmacological stimulation and inhibition of the beta-2 receptor plus knockdown of ADRB1, ADRB2 and ADRB3 in human brown adipocytes all confirmed that brown adipose lipolysis and thermogenesis occur through beta-2 receptor signaling in humans.

Participants / model
Human participants and human brown adipocytes
Treatment
Oral mirabegron in humans; receptor agonists, antagonists and knockdown in human brown adipocytes
Follow-up
not stated in the source
Study design
Original human and cell study
Funding
not stated in the source

This is mirabegron, not CL-316,243. It explains why rodent beta-3 results did not carry over.

Read the original source
Mirabegron meta-analysis (different compound): 6 studies, brown fat volume and glucose unchanged

Systematic review and meta-analysis

Ma L et al. Eur J Clin Pharmacol. 2024;80(3):317-333. PMID 38159219.

A systematic review and meta-analysis searched four databases to March 2023, reviewed 10 papers and included 6 in the meta-analysis. There were no significant changes in brown adipose tissue volume (p=0.72) or blood glucose (p=0.52) with mirabegron compared with placebo or pre-dose. The abstract reports increases in brown adipose tissue activity (p<0.01), blood non-esterified fatty acids (p<0.01), body temperature (p<0.01), resting energy expenditure (p<0.01), heart rate (p<0.01), diastolic blood pressure (p<0.01) and blood insulin (p<0.01).

Participants / model
Participants across 6 studies pooled in meta-analysis
Treatment
Oral mirabegron
Follow-up
Studies searched to March 2023
Study design
Systematic review and meta-analysis
Funding
not stated in the source

This is mirabegron, not CL-316,243. The abstract's systolic blood pressure entry is listed with the increases but carries p=0.25, so it is not quoted.

Read the original source
TAK-677 trial (different compound): 65 obese adults, 29 days, no weight or fat change

Randomized controlled trial

Redman LM et al. J Clin Endocrinol Metab. 2007;92(2):527-31. PMID 17118998.

Sixty-five obese men and women (BMI 33.9 +/- 2.1 kg/m2, age 31.4 +/- 0.9 years) were randomized to TAK-677 0.1 mg twice daily (n=21), 0.5 mg twice daily (n=22) or placebo twice daily (n=22) for 29 days. The drug was well tolerated, but heart rate was elevated by 9 +/- 2 beats per minute at the 0.5 mg twice-daily dose. After 28 days there was no change in 24-hour respiratory quotient at either dose (P=0.1 and P=1.0). The 0.5 mg twice-daily dose produced a small increase in 24-hour energy expenditure versus placebo, a change from baseline of 13 +/- 17 versus -39 +/- 18 kcal per day (P<0.05). Changes in weight, fat-free mass and visceral or subcutaneous abdominal fat depots did not differ between the three groups, nor did fasting insulin, free fatty acid or glucose. The acute studies showed large interindividual variability in plasma concentrations, which the authors say indicates possible problems with bioavailability and therefore efficacy.

Participants / model
65 obese men and women
Treatment
Oral TAK-677, 0.1 or 0.5 mg twice daily, or placebo
Follow-up
29 days
Study design
Randomized placebo-controlled trial
Funding
not stated in the source

This is TAK-677, a different beta-3 agonist, not CL-316,243.

Read the original source
Mice: glucose-lowering effect fades with repeated treatment, thermogenic effect did not

Animal study

Medak KD et al. Physiol Rep. 2022;10(4):e15187. PMID 35179321.

Repeated activation of the beta-3 receptor with CL 316,243 remodels white adipose tissue with increased mitochondrial enzymes and UCP1 expression, but the acute effects had been studied mostly in treatment-naive animals at room temperature. Under thermoneutral housing, the acute effects of CL to increase serum fatty acids and insulin and reduce blood glucose, but not the increase in energy expenditure, were attenuated in mice after repeated treatment, in parallel with reduced indices of protein kinase A signaling in white adipose tissue including phosphorylation of hormone sensitive lipase. The attenuation was confirmed in high-fat fed mice and in UCP1 knockout mice, and was rescued by the phosphodiesterase inhibitor cilostamide.

Participants / model
Mice, including high-fat fed and UCP1 knockout, under thermoneutral housing
Treatment
Repeated CL 316,243 treatment, with and without cilostamide; route and dose not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Mouse findings. The glucose-lowering effect fades with repeated use; the thermogenic effect did not in this model.

Read the original source
2008 review: beta-3 agonists did not become obesity or diabetes drugs

Human study

Arch JR. Naunyn Schmiedebergs Arch Pharmacol. 2008;378(2):225-40. PMID 18612674.

A review states that although beta-3 adrenoceptor agonists have not become drugs for the treatment of obesity or diabetes, they offer perspectives on obesity drug discovery. Some beta-3 agonists also stimulate other beta receptors in humans. The author notes that the beta-3 receptor can display variable pharmacologies of its own depending on the radioligand used in binding studies or the functional response measured, and that studies on this receptor demonstrate the difficulty of predicting the in vivo effects of agonist drugs from in vitro data.

Participants / model
Published beta-3 agonist programs, not a population
Treatment
Not applicable
Follow-up
not stated in the source
Study design
Narrative review
Funding
not stated in the source

A summary of development history and receptor pharmacology, not a primary study.

Read the original source
1995 review: CL 316,243 is a selective, potent beta-3 agonist; receptor pharmacology varies by species

Cell study

Pietri-Rouxel F et al. Fundam Clin Pharmacol. 1995;9(3):211-8. PMID 7557816.

A review of beta-3 adrenergic receptor pharmacology, drawing largely on stably transfected Chinese hamster ovary cells, discusses the structure and function of the receptor in various species and presents findings on ligands including CL 316,243, which was found to be a selective and potent beta-3 receptor agonist. Species-related variations in beta-3 receptor pharmacology were shown for propranolol and bupranolol.

Participants / model
Transfected Chinese hamster ovary cells and receptors from various species
Treatment
Cell culture binding and function; not a therapeutic route
Follow-up
not stated in the source
Study design
Review with original findings
Funding
not stated in the source

Cell findings. The receptor's pharmacology varies between species, which is why a rodent dose-response does not predict a human one.

Read the original source

Why is CL-316243 in D tier?

D fits a compound with one human trial, 10 treated men for 8 weeks, that found no change in body weight or body composition. The reason is known: human brown fat thermogenesis runs through the beta-2 receptor, not beta-3, and the beta-3 receptor's pharmacology differs between species. Insulin sensitivity improved at 4 weeks and diminished by 8 as plasma concentrations fell, so the supplier's fat-loss claim holds for rats and not for people.