Journal article

Synthesis and Pharmacological Evaluation of Heterocyclic Carboxamides: Positive Allosteric Modulators of the M-1 Muscarinic Acetylcholine Receptor with Weak Agonist Activity and Diverse Modulatory Profiles

Juliana CC Dallagnol, Elham Khajehali, Emma T van der Westhuizen, Manuela Jorg, Celine Valant, Alan G Goncalves, Ben Capuano, Arthur Christopoulos, Peter J Scammells

JOURNAL OF MEDICINAL CHEMISTRY | AMER CHEMICAL SOC | Published : 2018

Abstract

Targeting allosteric sites at M1 muscarinic acetylcholine receptors is a promising strategy for the treatment of Alzheimer's disease. Positive allosteric modulators not only may potentiate binding and/or signaling of the endogenous agonist acetylcholine (ACh) but also may possess direct agonist activity (thus referred to as PAM-agonists). Recent studies suggest that PAM-agonists with robust intrinsic efficacy are more likely to produce adverse effects in vivo. Herein we present the synthesis and pharmacological evaluation of a series of pyrrole-3-carboxamides with a diverse range of allosteric profiles. We proposed structural modifications at top, core, or pendant moieties of a prototypical ..

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Grants

Awarded by Australian Research Council


Awarded by National Health and Medicinal Research Council (NHMRC) of Australia


Funding Acknowledgements

This research was supported by Discovery Grant DP110100687 of the Australian Research Council as well as Program Grant APP1055134 of the National Health and Medicinal Research Council (NHMRC) of Australia. A.C. is a Senior Principal Research Fellow of the NHMRC. J.C.C.D. thanks the CNPq (National Council for Scientific and Technological Development of Brazil) for a scholarship.