結合協調性の低いM<sub>1</sub>ポジティブアロステリックモジュレーターTAK-071は、げっ歯類でコリン作動性副作用を軽減しつつ優れた認知機能亢進作用を示す

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  • TAK-071, a novel M<sub>1</sub> positive allosteric modulator with low cooperativity, improves cognitive function in rodents with few cholinergic side effects

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<p>The muscarinic M1 receptor (M1R) is a promising target for treating cognitive impairment associated with cholinergic deficits. We found that cooperativity (α-value) was key to lowering the risk of diarrhea by M1R positive allosteric modulators (M1 PAMs), and discovered a low α-value M1 PAM, TAK-071 with α-value of 199 and inflection point (IP) of 2.7 nM. T-662, a reference M1 PAM with high α-value of 1786 and IP of 0.62 nM, but not TAK-071, augmented isolated ileum motility. TAK-071 and T-662 improved scopolamine-induced cognitive deficits in rats at 0.3 and 0.1 mg/kg, respectively, and induced diarrhea at 10 mg/kg and 0.1 mg/kg, respectively, in rats. TAK-071 might have a wider margin between cognitive improvement and diarrhea induction than T-662. M1R activation 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 new therapeutic opportunities for cognitive dysfunction with minimum cholinergic side effects.</p>

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