jm7b00385_si_001.pdf (553.93 kB)
Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5‑HT2C Receptor Agonists
journal contribution
posted on 2017-06-21, 00:00 authored by Joseph Carpenter, Ying Wang, Gang Wu, Jianxin Feng, Xiang-Yang Ye, Christian L. Morales, Matthias Broekema, Karen A. Rossi, Keith J. Miller, Brian J. Murphy, Ginger Wu, Sarah E. Malmstrom, Anthony V. Azzara, Philip M. Sher, John M. Fevig, Andrew Alt, Robert L. Bertekap, Mary Jane Cullen, Timothy M. Harper, Kimberly Foster, Emily Luk, Qian Xiang, Mary F. Grubb, Jeffrey A. Robl, Dean A. WackerAgonism 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.
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Keywords
screening paradigmfood intakeOral administrationweight reduction5- HT 2 B receptor subtypespyrazol -5-ylsix-membered heterocyclesside effectsagonist structuresnonbasic heterocyclic amide agonists5- HT 2 CSAR investigationsad libitumActive Site Mutant ReceptorD 134A5- HT 2 C antagonist5- HT 2 B receptorsscreening hits5- HT 2novel class5- HT 2 C receptorsafety concerns
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