T-495, a novel low cooperative M₁ receptor positive allosteric modulator, improves memory deficits associated with cholinergic dysfunction and is characterized by low gastrointestinal side effect risk.

ABSTRACT: M₁ muscarinic acetylcholine receptor (M₁ R) activation can be a new therapeutic approach for the treatment of cognitive deficits associated with cholinergic hypofunction. However, M₁ R activation causes gastrointestinal (GI) side effects in animals. We previously found that an M₁ R positive allosteric modulator (PAM) with lower cooperativity (α-value) has a limited impact on ileum contraction and can produce a wider margin between cognitive improvement and GI side effects. In fact, TAK-071, a novel M₁ R PAM with low cooperativity (α-value of 199), improved scopolamine-induced cognitive deficits with a wider margin against GI side effects than a high cooperative M₁ R PAM, T-662 (α-value of 1786), in rats. Here, we describe th

SUBMITTER: Mandai T 

PROVIDER: S-EPMC6986443 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature