Premium
Discovery of Novel Muscarinic Receptor Modulators by Integrating a Natural Product Framework and a Bioactive Molecule
Author(s) -
Varkhedkar Rajesh,
Dogra Shalini,
Tiwari Divya,
Hussain Yusuf,
Yadav Prem Narayan,
Pandey Ganesh
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800001
Subject(s) - muscarinic acetylcholine receptor , natural product , chemistry , agonist , receptor , small molecule , pharmacology , neuroscience , computational biology , combinatorial chemistry , biology , biochemistry
Abstract Muscarinic acetylcholine receptors (mAChRs) are important therapeutic targets for several diseases of the central nervous system and periphery. However, the lack of subtype‐selective ligands for these receptors is a major challenge. A novel approach involving the integration of a natural product framework with a bioactive molecule ( i NPBM) by using gephyrotoxin and the isoindoline framework is demonstrated for the discovery of new and selective mAChR modulators. We established a scalable and versatile synthetic scheme to enable the synthesis of various analogues that provided the first structure–activity relationship study of this class of compounds. Pharmacological profiling of these compounds demonstrated several ligands with high affinity and selectivity for mAChRs. Specifically, RG‐06 and RG‐09 were found to be antagonists of M3‐mAChR, whereas RG‐02 was found to be an agonist at M2‐mAChR. Furthermore, RG‐02 exhibited salutary effects in an established pharmacological model of a cognitive deficit in mice.