Selective Agents for Serotonin2C (5-HT2C) Receptor

Abstract

The serotonin2C (5-HT2C) receptor has attracted a lot of attention owing to its role in appetite regulation, depression, obsessive-compulsive disorder (OCD), panic disorders, and substance abuse. This review summarizes non-patent and patent literature up to November 2005 that deals with the synthesis and characterization of selective 5-HT2C receptor agonists and antagonists. Highlights on structure-activity relationships have been included, when possible.

Regioselective alkylation of 1,3,4,5-tetrahydrobenzo[d]azepin-2-one and biological evaluation of the resulting alkylated products as potentially selective $$\hbox {5-HT}_{\mathrm{2C}}$$ 5-HT 2 C agonists

“…The carbonyl (2-one) group of compound 20 was found to improve the stability of the complex by forming hydrogen bond with Tyr358. Alongside the results obtained in biological evaluation of the test compounds (15,17,20), this computational approach also indicates that these compounds have appreciable affinity for 5-HT 2C receptors.…”

“…The same or different alkyl group could also be introduced at C 1 to offer tri-substituted derivatives 16 and 17 in the presence of NaH. Mono-(7, 10-12) or di-alkylation (19,20) at C 1 position could also be achieved using the N-methylated derivative 2 as the starting azepine in the presence of excess NaH. In a nutshell, by utilizing a suitable base and reaction condition, selective mono-/di-/tri-alkylation at C 1 and/or N 3 -positions of 3-benzazepin-2-one has been achieved to yield the desired products.…”

“…3-Methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one (2) (1 mmol) was added, and the reaction mixture was allowed to stir for 30 min. For preparation of the mono-C 1 -alkylated products (7, 10-12), 1 mmol of the alkyl halide (R 1 X) was added into the reaction mixture, while for the C 1 di-alkylated products (19,20), 2 mmol of the alkyl halide (R 1 X = R 2 X) was added. The reaction mixture was stirred for 1.5 h, and the reaction was monitored by TLC (hexane/Et 2 O 2:1).…”

“…Several small-size 5-HT 2C agonists have been reported to be in the early stages of clinical development [19,20]. Recently, an FDA panel approved lorcaserin for obesity treatment with some restrictions and careful patient monitoring.…”

Synthesis and structure–affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes

“…One of these structures identified as 6-bromo-2′-de-N-methylaplysinopsin ((Figure 1B), exhibited considerably higher affinity (>40-fold) for the 5-HT2C receptor than the 5-HT2A receptor5. This is of interest, because finding structurally simple small molecule pharmacophores that can distinguish between the closely related and clinically important 5-HT2A and 5-HT2C receptor subtypes has remained a challenge 12. Here we report on the synthesis of a library of novel aplysinopsin derivatives and their structure-affinity relationships for cloned human serotonin 5-HT2A and 5-HT2C receptors as well as another closely related and clinically important serotonin receptor subtype, the 5-HT1A receptor.…”