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 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.
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Acknowledgements
We thank Dr. Koji Murakami, Ms. Noriko Suzuki, and Mr. Yuuichi Arakawa for performing the NORT; Dr. Takayuki Niimura and Dr. Katsuya Sakimura for performing IP1 screening; Mr. Yuto Hiura, Ms. Maki Miyamoto, Mr. Yasuyuki Debori, Mr. Akihiko Goto, and Dr. Hisao Shimizu for performing the pharmacokinetic analysis of test compounds; Dr. Hiroki Sakamoto for helpful discussions regarding synthesis of compounds; Mr. Minoru Nakamura for providing chemical compounds; and Dr. Ceri H Davies for helpful discussions regarding electrophysiology assay design. The authors are employees of Takeda Pharmaceutical Company Limited. This work was supported by Takeda Pharmaceutical Company Limited.
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Sako, Y., Kurimoto, E., Mandai, T. et al. TAK-071, a novel M1 positive allosteric modulator with low cooperativity, improves cognitive function in rodents with few cholinergic side effects. Neuropsychopharmacol. 44, 950–960 (2019). https://doi.org/10.1038/s41386-018-0168-8
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DOI: https://doi.org/10.1038/s41386-018-0168-8
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