The 5-HT2C receptor (5HT2CR) was identified in 1986 and is widely expressed in the CNS . Several lines of evidence support a role for this receptor in body weight regulation. KO mice exhibit a phenotype characterized by increased body weight relative to wild-type littermates (average of 13% increase), increased food intake, and a significantly greater percentage of adipose tissue (48% increase) . The non-selective 5HT2CR agonist mCPP was found to reduce food intake in wild-type mice, but not in 5HT2CR KO mice. Furthermore, the 5-HT-releasing compound d-fenfluramine, which inhibited food intake in both rodents and man, was shown to have weaker anorectic activity in 5HT2CR KO mice . At least one 5HT2CR agonist has been reported to be in clinical development as described in a 2006 review of the medicinal chemistry in this area .
The anti-obesity effects of several different 5HT2CR agonists have been recently reported. The tetracyclic analog 45 (WAY163909) is a novel 5HT2CR full agonist that was discovered by using a pharmacophoric model for 5HT2CR binding activity. Compound 45 showed greater than 20-fold binding selectivity for 5HT2 CR over both 5HT2A receptor (5HT2AR) and the 5HT2B receptor (5HT2BR) . Functionally, the compound stimulated intracellular calcium mobilization with an EC50 value of 8nM. It showed no agonist activity at 5HT2AR, but partial agonist activity at 5HT2BR (EC50 = 185 nM, Emax = 40%). It also pro duced dose-dependent reductions in food intake in normal SD rats, an effect blocked by a 5HT2CR antagonist. In a 10-day study, 45 caused a 56% decrease in body weight, with reductions also observed in triglyceride levels. No toleration of the anorectic effect was observed, in contrast to studies with other 5HT2CR agonists .
The non-selective tricyclic derivative hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a] pyrazine 46 was used as a starting point for the discovery of a selective 5HT2C receptor agonist in the same series . Introduction of a methyl group on the piperazinyl ring in the core heterocycle and separation of the 4R,10aR di astereomer provided compounds with good 5HT2CR binding, but little subtype selectivity. Variation of the substituent arrangement on the aryl group improved the binding selectivity. An analog 47 was identified that showed greater than 10-fold selectivity for 5HT2CR (K = 1.9 nM) compared to either 5HT2AR (K = 40 nM) or 5HT2BR (K = 19 nM). This compound was shown to reduce food intake in a dose-dependent manner in a fasting-induced re-feeding model in Wistar rats (MED = 10mg/kg po).
Several issues were identified with 47 including phospholipidosis and hERG activity (IC50 = 2.5 mM), attributed to the lipophilicity and amphiphilicity of the core heterocycle . Replacement of the tricyclic ring in 47 with a hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine group resulted in compounds such as 48 with reduced hERG activity and 20- and 48-fold binding selectivity for 5HT2CR over 5HT2AR and 5HT2BR. Compound 48 was also shown to decrease 2 h food intake in a fasting-induced re-feeding model in Wistar rats in a dose-dependent manner, with a MED of 10mg/kg po, an effect antagonized by the 5HT2CR antagonist
Several new 5HT2CR chemotypes have recently been disclosed in the patent application literature. A tricyclic compound 49 was reported to exhibit high selectivity for 5HT2CR over the other subtypes . A bicyclic dihydrobenzofuranyl alkanamine 50 was also claimed to exhibit high binding affinity for 5HT2CR, with a K value of 1.1 nM .
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