CL 316243 disodium salt

EC50: (3.0±0.3) X 10-8 M for β3 adrenoceptor [1].

Benzodioxole-containing phenethanolamine CL-316,243 is a murine-selective β3 adrenoceptor agonist which can correct obesity and elevated blood glucose in diabetic rodents, which offers an exciting possibility for the treatment of non-insulin-dependent diabetes as well as obesity without undesired β-mediated side effects [3]. β3 adrenoceptor is located mainly in adipose tissue and is involved in the regulation of lipolysis and thermogenesis.

In vitro: The compound was a potent stimulant of rat adipocyte lipolysis (β3 effect, EC50 = (3.0±0.3) X 10-8 M), had no effect on the rate of contraction of guinea pig atria (β1 effect, EC50 > 10-4 M), and had only a very limited ability to inhibit insulin-stimulated [14C] glucose incorporation into glycogen in isolated rat soleus muacle (β2 effect, IC50 = (3.0±1.0) X 10-5 M) [1].

In vivo: In rat, CL-316,243 treatment resulted in increased growth rates and significant changes in food consumption at the end of the 10-day treatment period. CL-316,243 treatment increased insulin responsiveness and sensitivity in non-insulin-resistant rodent species. The CL-316,243 induced increases in whole-body glucose disposal were due entirely to increases in adipose tissue glucose uptake, while muscle glucose uptake remained unaltered [2].

Clinical trial: So far, no clinical study has been conducted.

References:
[1] Bloom JD, Dutia MD, Johnson BD, Wissner A, Burns MG, Largis EE, Dolan JA, Claus TH.  Disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino] propyl]-1,3-benzodioxole-2,2-dicar
-boxylate (CL 316,243).  A potent beta-adrenergic agonist virtually specific for beta 3 receptors. A promising antidiabetic and antiobesity agent. J Med Chem. 1992 Aug 7;35(16):3081-4.
[2] de Souza CJ, Hirshman MF, Horton ES.  CL-316,243, a beta3-specific adrenoceptor agonist, enhances insulin-stimulated glucose disposal in nonobese rats. Diabetes. 1997 Aug;46(8):1257-63.
[3] Kumar A, Shiloach J, Betenbaugh MJ, Gallagher EJ.  The beta-3 adrenergic agonist (CL-316,243) restores the expression of down-regulated fatty acid oxidation genes in type 2 diabetic mice. Nutr Metab (Lond). 2015 Mar 8;12:8.

Efficacy of the beta3-adrenergic receptor agonist CL-316243 on experimental bladder hyperreflexia and detrusor instability in the rat.[Pubmed:11490313]

J Urol. 2001 Sep;166(3):1142-7.

PURPOSE: Recent evidence indicates that in a number of species detrusor relaxation is mediated through activation of the beta3-adrenergic receptor. We determined whether activation of the beta3-adrenergic receptor would be a useful therapeutic approach for bladder instability. We profiled in vitro activity of the beta3-adrenergic receptor agonist CL-616243 and the efficacy of this compound in experimental models of detrusor instability and bladder hyperreflexia. MATERIALS AND METHODS: Isolated rat detrusor strips were contracted by depolarizing the preparations with 20 mM. KCl. CL-316423 was added to the tissue bath in increasing concentrations and contraction inhibition was assessed. Efficacy against bladder instability was evaluated using the obstructed hypertrophied bladder model in the rat. The acetic acid bladder cystometry model was used to assess the efficacy of CL-316423 in bladder hyperreflexia. Isovolumetric contractions were evoked by electrical stimulation using a silver bipolar electrode. Data are expressed as the mean plus or minus standard error of mean. RESULTS: CL-316243 inhibited spontaneously contracting, isolated rat detrusor strips in a concentration dependent manner with a mean concentration inhibiting 50% of maximal response of 2.65 +/- 0.36 nM. Intrinsic activity relative to forskolin was 1. In vivo CL-316243 administered intravenously or orally significantly increased the voiding interval and bladder compliance. In addition, there was a decrease in the number of spontaneous contractions during the filling phase in a model of neurogenic and obstruction induced bladder instability. The amplitude of electrically evoked isovolumetric contractions was significantly smaller after CL-316243 exposure. CONCLUSIONS: These data suggest that activating the beta3-adrenergic receptor in rat bladder using CL-316243 may directly inhibit smooth muscle contractility, experimental hyperreflexia and detrusor instability, and be useful for urge urinary incontinence.

Anti-obesity and anti-diabetic effects of CL 316,243, a highly specific beta 3-adrenoceptor agonist, in yellow KK mice.[Pubmed:8309351]

Life Sci. 1994;54(7):491-8.

The anti-obesity and anti-diabetic effects of CL 316,243, a highly specific beta 3-adrenoceptor agonist (beta 1: beta 2: beta 3 = 0:1:100,000), were evaluated in obese diabetic yellow KK mice and C57Bl control mice. The study compound was fed through a gastric tube at a rate of 0.1 mg/kg/day for 2 weeks. The following parameters were compared in the treated and control animals given distilled water: brown adipose tissue thermogenesis, resting metabolic rate, insulin receptors in adipocytes, and blood glucose and serum insulin levels during a glucose overloading test. CL 316,243 significantly increased brown adipose tissue thermogenesis and resting metabolic rate in both yellow KK mice and C57Bl controls. The amount of white adipose tissue decreased, although food intake was not affected. The effects contributed to the mitigation of obesity in yellow KK mice. CL 316,243 also increased the concentration of insulin receptors and decreased the levels of serum insulin and blood glucose during the glucose overloading test in yellow KK mice. These observations suggest that CL 316,243 possesses anti-obesity and anti-diabetic effects and consequently may be useful for treating obesity as well as non-insulin-dependent diabetes mellitus in obese persons, without causing excessive side effects.