期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 7, 页码 2875-2894出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01812
关键词
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资金
- Australian Research Council [DP110100687]
- National Health and Medicinal Research Council (NHMRC) of Australia [APP1055134]
- CNPq (National Council for Scientific and Technological Development of Brazil)
Targeting allosteric sites at M-1 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 molecule. Although generally there was a correlation between the degree of agonist activity and the modulatory potency of the PAMs, some derivatives displayed weak intrinsic efficacy yet maintained strong allosteric modulation. We also identified molecules with the ability to potentiate mainly the affinity or both affinity and efficacy of ACh.
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