The increasing prevalence of obesity represents a great burden on global human health. Obesity and its co-morbidities, such as type II diabetes, coronary heart disease, heart failure, and stroke, accounts for a growing number of worldwide deaths each year. Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically-proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side-effects and major safety concerns. We have developed a new screening paradigm which utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. This protocol successfully enabled the discovery of a series of heterocycles which exhibited good potency at 5-HT2C. With few exceptions, these compounds have excellent subtype functional selectivity against the closely related 5-HT2B and 5-HT2A receptors. Moreover, these compounds represent a significant structural divergence from what has typically been considered a requisite for agonism of the 5-HT2C receptor, namely exclusion of the basic amine that is proposed to interact with the active site Asp134 residue. Further optimization through replacement of an amide moiety with a variety of 5- and 6-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine. Oral administration of this compound to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist. These results, combined with promising in vitro and in vivo profiles, make the discovered compounds attractive candidates for further investigation. This unique structural series may enable the field to develop agonists with improved efficacy, tolerability and toxicity profiles compared to presently known 5-HT2C agonists.

Utilization of an active site mutant receptor for the identification of potent and selective atypical 5-HT2C receptor agonists

255th National Meeting (2018)

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