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

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 inositol monophosphate production through M₁R activation and improved scopolamine-induced cognitive deficits in rats at 0.3 and 0.1 mg/kg, respectively. TAK-071 and T-662 also induced diarrhea at 10 and 0.1 mg/kg, respectively, in rats. Thus, taking into consideration the fourfold lower brain penetration ratio of T-662, TAK-071 had a wider margin between cognitive improvement and diarrhea induction than T-662. Activation of M₁R increases neural excitability via membrane depolarization, reduced afterhyperpolarization, and generation of afterdepolarization in prefrontal cortical pyramidal neurons. T-662 induced all three processes, whereas TAK-071 selectively induced afterdepolarization. Combining sub-effective doses of TAK-071, but not T-662, with an acetylcholinesterase inhibitor, significantly ameliorated scopolamine-induced cognitive deficits in rats. TAK-071 may therefore provide therapeutic opportunities for cognitive dysfunction related to cholinergic deficits or reduced M₁R expression, while minimizing peripheral cholinergic side effects.