ABSTRACT
A novel series of 1,6-dihydro-2H-indeno[5,4-b]furan derivatives were designed and synthesized as MT(2)-selective ligands. This scaffold was identified as a potent mimic of the 5-methoxy indole core of melatonin, and introduction of a cyclohexylmethyl group at the 7-position of this scaffold afforded an MT(2)-selective ligand 15 (K(i) = 0.012 nM) with high MT(1)/MT(2) selectivity (799). Compound 15 was identified as a potent full agonist for the MT(2) subtype and exhibited reentrainment effects to a new light/dark cycle in ICR mice at 3-30 mg/kg. This result demonstrated the involvement of the MT(2) receptors in chronobiotic activity.
Subject(s)
Acetamides/chemical synthesis , Benzofurans/chemical synthesis , Receptor, Melatonin, MT2/agonists , Acetamides/chemistry , Acetamides/pharmacology , Animals , Benzofurans/chemistry , Benzofurans/pharmacology , CHO Cells , Circadian Rhythm , Cricetinae , Cricetulus , Cyclic AMP/biosynthesis , Darkness , Humans , Ligands , Light , Male , Mice , Mice, Inbred ICR , Motor Activity/drug effects , Radioligand Assay , Receptor, Melatonin, MT1/agonists , Structure-Activity RelationshipSubject(s)
Indenes/administration & dosage , Receptors, Melatonin/agonists , Sleep Initiation and Maintenance Disorders/drug therapy , Animals , Chronic Disease , Cyclic AMP/metabolism , Drug Evaluation, Preclinical , Humans , Indenes/adverse effects , Indenes/pharmacology , Randomized Controlled Trials as Topic , Sleep Stages/drug effects , Substance-Related Disorders , Suprachiasmatic Nucleus/drug effects , Suprachiasmatic Nucleus/physiologyABSTRACT
We investigated the effects of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4]furan-8-yl)ethyl]propionamide (ramelteon, TAK-375), a novel MT1/MT2 receptor agonist, on nocturnal sleep in freely moving monkeys and compared these results with those of melatonin and zolpidem. Treatment with ramelteon (0.03 and 0.3 mg/kg, p.o.) significantly shortened latency to sleep onset and significantly increased total duration of sleep. Treatment with melatonin (0.3, 1, and 3 mg/kg, p.o.) also decreased sleep latency, but the effect was weak; the only significant reduction was seen with the 0.3 mg/kg dose on latency to light sleep. Melatonin had no significant effects on the duration of sleep. Zolpidem had no significant effects on latency to sleep onset in this study at any dose (1, 3, 10, and 30 mg/kg, p.o.). The highest dose (30 mg/kg) of zolpidem had a tendency to increase slow wave sleep; however, it also induced apparent sedation and myorelaxation. Treatment with ramelteon and melatonin had no evident effect on the general behavior of the monkeys. Spectral analysis (fast Fourier transform, FFT) of both ramelteon and melatonin revealed sleep patterns that were indistinguishable from those of naturally occurring sleep. The EEG power spectra of zolpidem were qualitatively different from that of naturally occurring physiological sleep. Results of the present study support the investigation of ramelteon as a sleep-promoting agent in humans.
