The antiobesity action of (S)-(+)-1-(4-chlorophenylthiomethyl)-N-methylethylamine fumarate (AO-124).
The antiobesity effects of (S)-(+)-1-(4-chlorophenylthiomethyl)-N-methylethylamine fumarate (AO-124) were examined in rats and dogs. AO-124 suppressed food intake dose dependently in normal, Zucker fatty and VMH-obese rats, and beagle dogs. Its anorectic activity was not altered by pretreatment with methysergide, a serotonin receptor blocker. AO-124 also reduced the hyperphagia induced by 2-deoxy-D-glucose but not that induced by insulin, noradrenaline or muscimol, suggesting that the anoretic mechanism of AO-124 may be implicated in a glucostatic regulatory system of feeding. In addition, AO-124 decreased insulin secretion in response to an oral, but not an intravenous, glucose load. Such a suppression in insulin secretion may be explained by slow absorption of glucose from the intestine: AO-124 delayed the gastric emptying time of glucose and inhibited the active transport of glucose as observed in the everted small intestine. Two week administration of AO-124 to Zucker fatty rats resulted in a significant reduction of plasma insulin levels, body weight gain, and body lipid without exerting any changes in body protein. These findings indicate that AO-124 may be useful as an antibesity agent on the basis of its unique mechanisms of action.
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D004285:Dogs; D005021:Ethylamines / Q000494:pharmacology*; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects; D005951:Glucose Tolerance Test; D007033:Hypothalamus, Middle / Q000502:physiology; D007421:Intestine, Small / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D011924:Rats, Zucker
D001067:Appetite Depressants; D005021:Ethylamines; D008055:Lipids; C049859:1-(4-chlorophenylthiomethyl)-N-methylethylamine fumarate; D008784:Methysergide