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 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.