{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:34:20Z","timestamp":1791398060743,"version":"4.3.3"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"37","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,9,15]]},"abstract":"<jats:p>\n                    The forebrain cholinergic system promotes higher brain function in part by signaling through the M\n                    <jats:sub>1<\/jats:sub>\n                    muscarinic acetylcholine receptor (mAChR). During Alzheimer's disease (AD), these cholinergic neurons degenerate, therefore selectively activating M\n                    <jats:sub>1<\/jats:sub>\n                    receptors could improve cognitive function in these patients while avoiding unwanted peripheral responses associated with non-selective muscarinic agonists. We describe here benzyl quinolone carboxylic acid (BQCA), a highly selective allosteric potentiator of the M\n                    <jats:sub>1<\/jats:sub>\n                    mAChR. BQCA reduces the concentration of ACh required to activate M\n                    <jats:sub>1<\/jats:sub>\n                    up to 129-fold with an inflection point value of 845 nM. No potentiation, agonism, or antagonism activity on other mAChRs is observed up to 100 \u03bcM. Furthermore studies in M\n                    <jats:sub arrange=\"stagger\">1<\/jats:sub>\n                    <jats:sup arrange=\"stagger\">\u2212\/\u2212<\/jats:sup>\n                    mice demonstrates that BQCA requires M\n                    <jats:sub>1<\/jats:sub>\n                    to promote inositol phosphate turnover in primary neurons and to increase c-fos and arc RNA expression and ERK phosphorylation in the brain. Radioligand-binding assays, molecular modeling, and site-directed mutagenesis experiments indicate that BQCA acts at an allosteric site involving residues Y179 and W400. BQCA reverses scopolamine-induced memory deficits in contextual fear conditioning, increases blood flow to the cerebral cortex, and increases wakefulness while reducing delta sleep. In contrast to M\n                    <jats:sub>1<\/jats:sub>\n                    allosteric agonists, which do not improve memory in scopolamine-challenged mice in contextual fear conditioning, BQCA induces \u03b2-arrestin recruitment to M\n                    <jats:sub>1<\/jats:sub>\n                    , suggesting a role for this signal transduction mechanism in the cholinergic modulation of memory. In summary, BQCA exploits an allosteric potentiation mechanism to provide selectivity for the M\n                    <jats:sub>1<\/jats:sub>\n                    receptor and represents a promising therapeutic strategy for cognitive disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0900903106","type":"journal-article","created":{"date-parts":[[2009,8,26]],"date-time":"2009-08-26T22:23:42Z","timestamp":1251325422000},"page":"15950-15955","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":269,"title":["Selective activation of the M\n                    <sub>1<\/sub>\n                    muscarinic acetylcholine receptor achieved by allosteric potentiation"],"prefix":"10.1073","volume":"106","author":[{"given":"Lei","family":"Ma","sequence":"first","affiliation":[{"name":"Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew 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