TAK-071, a novel M₁ positive allosteric modulator with low cooperativity, improves cognitive function in rodents with few cholinergic side effects.

ABSTRACT: The muscarinic M₁ receptor (M₁R) is a promising target for treating cognitive impairment associated with cholinergic deficits in disorders such as Alzheimer's disease and schizophrenia. We previously reported that cooperativity (α-value) was key to lowering the risk of diarrhea by M₁R positive allosteric modulators (M₁ PAMs). Based on this, we discovered a low α-value M₁ PAM, TAK-071 (α-value: 199), and characterized TAK-071 using T-662 as a reference M₁ PAM with high α-value of 1786. Both TAK-071 and T-662 were potent and highly selective M₁ PAMs, with inflection points of 2.7 and 0.62 nM, respectively. However, T-662 but not TAK-071 augmented isolated ileum motility. TAK-071 and T-662 increased hippocampal inosi

SUBMITTER: Sako Y 

PROVIDER: S-EPMC6461781 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature