Objective: Common therapies for insomnia or circadian rhythm sleep disorders (CRSDs) often have undesirable side effects related to activity at benzodiazepine or opiate receptors. TAK-375, a novel agent currently being evaluated in clinical trials for treatment of insomnia and CRSD, is a highly selective ML1 receptor agonist, exhibiting only weak affinity for ML2 receptors. In this study, we examined the binding affinities of TAK-375 and its active metabolite (M-II) to other potential active binding sites such as receptors for neurotransmitters, peptides, and cytokines, as well as ion channels and various enzymes. Specifically, we were interested in receptors known to affect cognitive function and abuse liability. Materials and Methods: Conventional binding assays were used to measure the affinities of TAK-375 and M-II for a large number of binding sites from a variety of tissues. Agents were initially tested at a concentration of 10 mM to measure displacement of a radiolabeled high-affinity ligand at the binding site of interest. If any binding was detected at this concentration, then other concentrations were tested to determine an approximate binding affinity. In addition, the ability of TAK-375 and M-II to interfere with any of a large number of enzyme activities was studied using well-characterized substrate reactions. Results: TAK-375 showed no measurable affinity for any of a large number of ligand binding sites, including benzodiazepine, dopamine, and opiate receptors. Although melatonin showed weak affinity for D1 and 5-HT1A receptors, TAK-375 showed no evidence of such binding. M-II showed affinity for only one site, the 5-HT2B receptor; however, the affinity was low (Ki, 1.75 mM). Such low-affinity binding is unlikely to have clinical relevance owing to the low concentrations of parent compound required for activation of ML1 receptors. Also, TAK-375 and M-II had no effect on any of various enzyme activities. Conclusion: TAK-375 is a highly selective agonist for ML1 receptors with no activity at any of a large number of other potential binding sites. These results are consistent with behavioral studies demonstrating that TAK-375 exerts sleep-promoting action without causing learning and memory impairment, motor dysfunction, and drug-abuse ability.
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