%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