In:
ChemMedChem, Wiley, Vol. 9, No. 8 ( 2014-08), p. 1677-1682
Abstract:
Of the five G‐protein‐coupled muscarinic acetylcholine receptors (mAChRs; M 1 –M 5 ), M 5 is the least explored and understood due to a lack of mAChR subtype‐selective ligands. We recently performed a high‐throughput functional screen and identified a number of weak antagonist hits that are selective for the M 5 receptor. Here, we report an iterative parallel synthesis and detailed molecular pharmacologic profiling effort that led to the discovery of the first highly selective, central nervous system (CNS)‐penetrant M 5 ‐orthosteric antagonist, with sub‐micromolar potency (hM 5 IC 50 =450 n M , hM 5 K i =340 n M , M 1 –M 4 IC 50 〉 30 μ M ), enantiospecific inhibition, and an acceptable drug metabolism and pharmacokinetics (DMPK) profile for in vitro and electrophysiology studies. This compound will be a powerful tool and molecular probe for the further investigation into the role of M 5 in addiction and other diseases.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201402051
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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