Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT2C Receptor Agonists

4 years ago

Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT2C Receptor Agonists

Brian J. Murphy, Ying Wang, Andrew Alt, Qian Xiang, Robert L. Bertekap, Timothy M. Harper, Philip M. Sher, Mary Jane Cullen, Karen A. Rossi, Kimberly Foster, Xiang-Yang Ye, Ginger Wu, Dean A. Wacker, Matthias Broekema, Emily Luk, Jeffrey A. Robl, Anthony V. Azzara, Sarah E. Malmstrom, Christian L. Morales, Mary F. Grubb, Jianxin Feng, John M. Fevig, Joseph Carpenter, Keith J. Miller, Gang Wu

Agonism of the 5-HT_2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT_2A and 5-HT_2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT_2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT_2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT_2C with high selectivity over the related 5-HT_2A and 5-HT_2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT_2C antagonist.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00385

DOI: 10.1021/acs.jmedchem.7b00385