%0 Journal Article %A Carpenter, Joseph %A Wang, Ying %A Wu, Gang %A Feng, Jianxin %A Ye, Xiang-Yang %A Morales, Christian L. %A Broekema, Matthias %A Rossi, Karen A. %A Miller, Keith J. %A Murphy, Brian J. %A Wu, Ginger %A Malmstrom, Sarah E. %A Azzara, Anthony V. %A Sher, Philip M. %A Fevig, John M. %A Alt, Andrew %A Bertekap, Robert L. %A Cullen, Mary Jane %A Harper, Timothy M. %A Foster, Kimberly %A Luk, Emily %A Xiang, Qian %A Grubb, Mary F. %A Robl, Jeffrey A. %A Wacker, Dean A. %D 2017 %T Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5‑HT2C Receptor Agonists %U https://acs.figshare.com/articles/journal_contribution/Utilization_of_an_Active_Site_Mutant_Receptor_for_the_Identification_of_Potent_and_Selective_Atypical_5_HT_sub_2C_sub_Receptor_Agonists/5181691 %R 10.1021/acs.jmedchem.7b00385.s001 %2 https://acs.figshare.com/ndownloader/files/8832250 %K screening paradigm %K food intake %K Oral administration %K weight reduction %K 5- HT 2 B receptor subtypes %K pyrazol -5-yl %K six-membered heterocycles %K side effects %K agonist structures %K nonbasic heterocyclic amide agonists %K 5- HT 2 C %K SAR investigations %K ad libitum %K Active Site Mutant Receptor %K D 134A %K 5- HT 2 C antagonist %K 5- HT 2 B receptors %K screening hits %K 5- HT 2 %K novel class %K 5- HT 2 C receptor %K safety concerns %X 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. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B 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-HT2C antagonist. %I ACS Publications