Discovery of Novel Muscarinic Receptor Modulators by Integrating a Natural Product Framework and a Bioactive Molecule

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 fra...

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Bibliographic Details
Published in:ChemMedChem 2018-02, Vol.13 (4), p.384-395
Main Authors: Varkhedkar, Rajesh, Dogra, Shalini, Tiwari, Divya, Hussain, Yusuf, Yadav, Prem Narayan, Pandey, Ganesh
Format: Article
Language:English
Subjects:
Acetylcholine receptors (muscarinic)
Antagonists
Biological activity
Central nervous system
Cognitive ability
drug design
drug discovery
Ligands
Modulators
Natural products
Pharmacology
Receptors
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Summary: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 (iNPBM) 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. Novel mAChR modulators by iNPBM: The framework of gephyrotoxin is integrated with substituted isoindolines to afford novel ligands with sub‐nanomolar affinity for muscarinic acetylcholine receptors (mAChRs). This could open up a promising approach for the discovery of drugs for pathophysiological conditions associated with mAChRs, such as Alzheimer's disease, schizophrenia, asthma, and chronic obstructive pulmonary diseases.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201800001