The endogenous opioid system has been known to regulate appetitive behavior for over 30 years . In preclinical species, both endogenous peptidic and non-peptidic opioid receptor agonists have exhibited orexigenic properties. Non-selective opioid receptor antagonists including naloxone have shown anorectic activity in rodents . Opiates mediate their activity through three subtypes called the m-, 8-, and k-opioid receptors . The m-opioid receptor plays an important role in feeding behavior since administration of the selective m-opioid agonist DAMGO within the nucleus accumbens selectively increases consumption of high fat food in rats . A selective opioid receptor antagonist naltrexone has produced mixed results in humans, having either efficacy or no efficacy in promoting weight loss [85-88].
Despite mixed results observed with antagonists in the clinic, the discovery of new selective or pan-selective opioid receptor some antagonists for use as potential weight loss agents has continued. A series of pan-selective opioid antagonists has been identified that reduce food intake and body weight in rodent models . The phenyl-piperidine antagonist 40 was not efficacious in rodent feeding models following oral administration, primarily because of extensive first pass metabolism . Removal of the aromatic hydroxyl group resulted in loss of potency. Replacement of the hydroxyl group with carbamoyl and carbamyl groups led to discovery of 41, a pan-selective antagonist with bioavailability of 32% in the rat. Compound 41 decreased food intake in fasted Long-Evans rats following a 3 mg/kg oral dose.
A series of structurally unrelated nicotinamide derivatives such as 42 has also been shown to exhibit m-, k-, and 8-opioid receptor antagonist activities and cause weight loss in rodent models of 41. Analogs have been recently described in a series of patent applications. Replacement of the carboxamide group in 42 with heterocyclic groups led to the identification of the 4,5-dihydro-1H-imidazolyl derivative 43 (GTP-y-35S K — 10, 34, and 120 nM at m-, k-, and 8-opioid receptors, respectively) . Introduction of an alkyl tether between the aryl rings in a diphenylether analog of 42 provided the tricyclic dibenzo[b,f]oxepine compound 44 which showed good functional activities at the different subtypes (GTP-g-35S Kb — 0.7, 2.2, and 2.1 nM at m-, k-, and 8-opioid receptors) .
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