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Discovery of M5 Muscarinic Acetylcholine Receptor Antagonists: 1‐Methyl‐4‐Phenylpiperidine Analogs
Author(s) -
Lee NaRa,
Zhang Xuan,
Darna Mahesh,
Zheng Guangrong,
Dwoskin Linda
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.768.17
Subject(s) - muscarinic acetylcholine receptor , chemistry , muscarinic acetylcholine receptor m3 , pharmacology , ventral tegmental area , nucleus accumbens , acetylcholine , antagonist , muscarinic acetylcholine receptor m4 , receptor , biochemistry , dopamine , medicine , dopaminergic
Ventral tegmental area (VTA) dopamine (DA) neurons project to nucleus accumbens (NAc) and are believed to mediate the rewarding effects of abused drugs. Stimulation of M5 muscarinic acetylcholine receptors (mAChRs) activates VTA DA neurons (Omelchenko N et al., 2006). M5 knockout mice exhibit reduced cocaine and morphine self‐administration (Fink‐Jensen et al., 2003; Basile et al., 2002). Microinfusion of scopolamine (M1‐M5 mAChRs antagonist) into VTA attenuates cocaine self‐administration (Solecki et al., 2013). Thus, M5 mAChR antagonists may be novel treatments for drug abuse. We evaluated a series of 1‐methyl‐4‐phenylpiperidine containing analogs as antagonists at M5 mAChRs. Affinity for 12 analogs at the [ 3 H]N‐methylscopolamine binding site was determined using Chinese hamster ovary cell membranes expressing human M1, M3 or M5 mAChRs. XZ‐11341a exhibited the highest affinity at M1, M3 and M5 mAChRs (Ki = 0.67 ± 0.08, 0.37 ± 0.04, 0.38 ± 0.011 µM, respectively). Generally, replacing the ester in with an amide reduced affinity at all subtypes. For example, XZ‐11343b (amide) had no affinity compared with XZ‐11343a (ester, moderate affinity) at M3 mAChRs. Replacing the carbamate moiety with a carbamide also attenuated affinity at all subtypes. Current insights regarding the SAR will direct future synthetic approaches towards identifying potent selective M5 mAChR antagonists (Supported by DA030667).