TAK-071, a novel M1 positive allosteric modulator with low cooperativity, improves cognitive function in rodents with few cholinergic side effects
| Autor: | Atsushi Suzuki, Haruhide Kimura, Motohisa Suzuki, Yuu Sako, Takao Mandai, Masami Yamada, Maiko Tanaka, Emi Kurimoto, Yuji Shimizu |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Diarrhea
Male Allosteric modulator medicine.drug_class Scopolamine Cholinergic Agents Muscarinic Antagonists Pharmacology Hippocampus Article Afterdepolarization Rats Sprague-Dawley Mice 03 medical and health sciences 0302 clinical medicine Muscarinic acetylcholine receptor medicine Animals Cognitive Dysfunction Rats Long-Evans Mice Knockout Mice Inbred ICR Chemistry Receptor Muscarinic M1 Afterhyperpolarization Depolarization Muscarinic acetylcholine receptor M1 Electrophysiological Phenomena Rats 030227 psychiatry Mice Inbred C57BL Psychiatry and Mental health Acetylcholinesterase inhibitor Cholinergic 030217 neurology & neurosurgery |
| Zdroj: | Neuropsychopharmacology. 44:950-960 |
| ISSN: | 1740-634X 0893-133X |
| Popis: | The muscarinic M(1) receptor (M(1)R) 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 M(1)R positive allosteric modulators (M(1) PAMs). Based on this, we discovered a low α-value M(1) PAM, TAK-071 (α-value: 199), and characterized TAK-071 using T-662 as a reference M(1) PAM with high α-value of 1786. Both TAK-071 and T-662 were potent and highly selective M(1) 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 M(1)R 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 M(1)R 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 M(1)R expression, while minimizing peripheral cholinergic side effects. |
| Databáze: | OpenAIRE |
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