Disease relevance of 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxy-ethyl]amino]propyl]benzo[1,3]dioxole-2,2-dicarboxylic acid

• Chronic administration of CL316243 to the A-ZIP/F-1 mice did not improve their thermogenesis, hyperglycemia, or hyperinsulinemia [1].
• Treatment with beta3a-Tp10 (1 microM) caused cAMP responses to CL316243 in the beta3a-adrenoceptor to become pertussis toxin-sensitive and display a 30% increase over control, whereas the other peptides did not affect any receptor [2].
• 1. The in vitro activity of four aryl propanolamines was compared to two prototypic beta3 receptor agonists, CGP 12177 and CL316243 at the human beta3 receptor, the rat beta3 receptor in the stomach fundus and receptors mediating atrial tachycardia [3].
• Further, thermogenesis in adipocytes was stimulated by CL316243, a beta3-adrenoceptor agonist being developed to treat obesity [4].

High impact information on 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxy-ethyl]amino]propyl]benzo[1,3]dioxole-2,2-dicarboxylic acid

• In contrast, m-/+ mice are hypometabolic at ambient temperature and eumetabolic at thermoneutrality M-/+ and wild-type mice have similar dose-response curves for metabolic response to a beta(3)-adrenergic agonist, CL316243, indicating normal sensitivity of adipose tissue to sympathetic stimulation [5].
• The aim of the study was to assess the role of a specific beta3 agonist (CL316243) on LES pressure (LESP) in vivo [6].
• The protective effects of the beta 3-adrenoceptor agonist CL316243 on this rat model and the mechanism of action were examined using histological techniques [7].
• The beta 3-adrenoceptor agonist CL316243 prevents indomethacin-induced jejunal ulceration in the rat by reversing early villous shortening [7].
• Here we provide evidence that, in a phosphatidyl inositol 3-kinase dependent manner, beta3-adrenergic stimulation (using CL316243) in adipocytes induces PKB phosphorylation in the absence of insulin and also potentiates insulin-induced phosphorylation of PKB [8].

Biological context of 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxy-ethyl]amino]propyl]benzo[1,3]dioxole-2,2-dicarboxylic acid

• In conscious monkeys and baboons, CL, 100 micrograms/kg, i.v., did not induce significant effects, whereas BRL, 83 micrograms/kg, i.v., increased heart rate (36 +/- 6%), LV dP/dt (85 +/- 9%) and decreased total peripheral resistance (30 +/- 2%) [9].
• In conscious dogs, CL, 10 micrograms/kg, i.v., reduced, P < .05, mean arterial pressure by 8 +/- 4% and total peripheral resistance by 51 +/- 4% and increased, P < .05, LV dP/dt by 79 +/- 10% and heart rate by 88 +/- 8% [9].
• 5. CL316243 increased Erk1/2 phosphorylation with pEC(50) values and maximum responses that were not significantly different in cells expressing either splice variant [10].
• In contrast, the effects of CL316243 (0.1 to 100 microgram./kg. intravenously) on mean blood pressure and heart rate were minimal [11].
• CONCLUSIONS: These results indicate that in cerebral infarcted rats detrusor hyperreflexia can be suppressed by the selective beta3-adrenoceptor agonist CL316243 without increasing post-void residual volume and without significant cardiovascular side effects [11].

Anatomical context of 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxy-ethyl]amino]propyl]benzo[1,3]dioxole-2,2-dicarboxylic acid

• In 3T3-F442A adipocytes, SR59230A antagonized CL316243-mediated increases of cAMP and had no agonist actions [12].
• Responses to CL316243 in ileum were unaffected by either treatment [13].
• Significantly higher numbers of Fos positive cells were found in the rats treated i.c.v. with CL316243 compared with control rats in the paraventricular hypothalamus, lateral hypothalamic area, ventromedial hypothalamic nucleus and dorsal hypothalamic area [14].

Associations of 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxy-ethyl]amino]propyl]benzo[1,3]dioxole-2,2-dicarboxylic acid with other chemical compounds

• BRL37344A and CL316243, selective beta3-adrenoceptor agonists and CGP-12177A (a selective beta3-adrenoceptor partial agonist and beta1-/beta2-adrenoceptor antagonist) relaxed detrusor preparations from the normal, low compliant and hyperreflexic groups when applied at concentrations greater than 10-6 M [15].
• The protein synthesis inhibitor, cycloheximide, did not inhibit CL316243-mediated thermogenesis [4].
• Adipocytes were exposed to rotenone, FCCP, cycloheximide. troglitazone, or CL316243 [4].

Gene context of 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxy-ethyl]amino]propyl]benzo[1,3]dioxole-2,2-dicarboxylic acid

• The metabolic activities of four types of beta3-adrenoceptor (AR) agonists, BRL35135A, BRL28410, ICI215001 and CL316243, were compared with those of other beta1- and beta2-AR agonists in rat white adipocytes [16].
• The beta3-adrenoceptor agonist CL316243 (CL) suppressed all the insulin actions in adenosine deaminase (ADA)-treated cells, but was without effect in non-ADA-treated cells [17].
• The beta(3)-AR agonists BRL37344, CL316243, GR265162X, L755507, SB251023, the non-conventional partial beta-AR agonist CGP12177 and the beta-AR agonist (-)-isoprenaline caused concentration-dependent increases in EAR in cells expressing either splice variant [10].
• We have conducted experiments investigating the effects of i.c.v. administration of the selective beta(3)-AR agonist CL316243 on Fos expression to determine whether beta(3)-AR stimulation affects neurones within specific brain nuclei [14].
• Prodrugs of CL316243: a selective beta3-adrenergic receptor agonist for treating obesity and diabetes [18].

References