1 research outputs found
Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5‑HT<sub>2C</sub> Receptor Agonists
Agonism of the 5-HT<sub>2C</sub> receptor
represents one of the most well-studied and clinically proven mechanisms
for pharmacological weight reduction. Selectivity over the closely
related 5-HT<sub>2A</sub> and 5-HT<sub>2B</sub> 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<sub>2C</sub> 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<sub>2C</sub>. SAR
investigations around the screening hits provided a diverse set of
potent agonists at 5-HT<sub>2C</sub> with high selectivity over the
related 5-HT<sub>2A</sub> and 5-HT<sub>2B</sub> 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)-1<i>H</i>-pyrazol-5-yl)Âpyridazin-3-amine
(<b>69</b>). Oral administration of <b>69</b> to rats
reduced food intake in an ad libitum feeding model, which could be
completely reversed by a selective 5-HT<sub>2C</sub> antagonist