{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T05:48:33Z","timestamp":1782884913701,"version":"3.54.5"},"reference-count":61,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T00:00:00Z","timestamp":1580169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>M<jats:sub>1<\/jats:sub> muscarinic acetylcholine receptor (M<jats:sub>1<\/jats:sub>R) activation can be a new therapeutic approach for the treatment of cognitive deficits associated with cholinergic hypofunction. However, M<jats:sub>1<\/jats:sub>R activation causes gastrointestinal (GI) side effects in animals. We previously found that an M<jats:sub>1<\/jats:sub>R positive allosteric modulator (PAM) with lower cooperativity (\u03b1\u2010value) has a limited impact on ileum contraction and can produce a wider margin between cognitive improvement and GI side effects. In fact, TAK\u2010071, a novel M<jats:sub>1<\/jats:sub>R PAM with low cooperativity (\u03b1\u2010value of 199), improved scopolamine\u2010induced cognitive deficits with a wider margin against GI side effects than a high cooperative M<jats:sub>1<\/jats:sub>R PAM, T\u2010662 (\u03b1\u2010value of 1786), in rats. Here, we describe the pharmacological characteristics of a novel low cooperative M<jats:sub>1<\/jats:sub>R PAM T\u2010495 (\u03b1\u2010value of 170), using the clinically tested higher cooperative M<jats:sub>1<\/jats:sub>R PAM MK\u20107622 (\u03b1\u2010value of 511) as a control. In rats, T\u2010495 caused diarrhea at a 100\u2010fold higher dose than that required for the improvement of scopolamine\u2010induced memory deficits. Contrastingly, MK\u20107622 showed memory improvement and induction of diarrhea at an equal dose. Combination of T\u2010495, but not of MK\u20107622, and donepezil at each sub\u2010effective dose improved scopolamine\u2010induced memory deficits. Additionally, in mice with reduced acetylcholine levels in the forebrain via overexpression of A53T \u03b1\u2010synuclein (ie, a mouse model of dementia with Lewy bodies and Parkinson's disease with dementia), T\u2010495, like donepezil, reversed the memory deficits in the contextual fear conditioning test and Y\u2010maze task. Thus, low cooperative M<jats:sub>1<\/jats:sub>R PAMs are promising agents for the treatment of memory deficits associated with cholinergic dysfunction.<\/jats:p>","DOI":"10.1002\/prp2.560","type":"journal-article","created":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T15:19:44Z","timestamp":1580224784000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["T\u2010495, a novel low cooperative M<sub>1<\/sub> receptor positive allosteric modulator, improves memory deficits associated with cholinergic dysfunction and is characterized by low gastrointestinal side effect risk"],"prefix":"10.1002","volume":"8","author":[{"given":"Takao","family":"Mandai","sequence":"first","affiliation":[{"name":"Neuroscience Drug Discovery Unit Research Takeda Pharmaceutical Company Limited Fujisawa 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