期刊
CHEMMEDCHEM
卷 13, 期 4, 页码 384-395出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201800001
关键词
biological activity; drug discovery; drug design; natural products; receptors
资金
- DST-JC Bose for fellowships
- UGC-New Delhi
- DST-Ramanujan fellowship
- DST-cognitive science initiative grant
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.
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