Nonphotic entrainment of the circadian body temperature rhythm by the selective ORL1 receptor agonist W-212393 in rats.
We synthesized a small-molecule opioid receptor-like 1 (ORL1) receptor agonist, 2-{3-[1-((1R)-acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzimidazol-1-yl}-N-methylacetamide (W-212393), and investigated its effect on the circadian body temperature rhythm of rats. W-212393 has high affinity for ORL1 receptors in the rat cerebral cortex and human ORL1 receptors expressed in HEK293 cells with K(i) values of 0.76 and 0.50 nM, respectively. W-212393 concentration-dependently stimulated GTPgamma(35)S binding and its efficacy was similar to nociceptin/orphanin FQ (N/OFQ), suggesting that W-212393 is a full agonist at ORL1 receptors. W-212393 dose-dependently occupied ORL1 receptors following intraventricular or intraperitoneal administration, suggesting that W-212393 is a brain-penetrating compound. W-212393 (100 nM) and N/OFQ (100 nM) significantly suppressed the activity of spontaneously firing rat suprachiasmatic nucleus neurons. These suppressive effects were blocked by an ORL1 receptor antagonist, J-113397 (1 microM). W-212393 (3 mg kg(-1), i.p.) induced a significant phase advance at circadian time 6 (CT6) and CT9, but not at other CTs. The magnitude of the W-212393 (0.3-3 mg kg(-1), i.p.)-induced phase advance was dose-dependent and greater than those produced by 8-hydroxy-2-(di-n-propylamino)tetralin (0.3-3 mg kg(-1), i.p.) or melatonin (0.3-3 mg kg(-1), i.p.). The W-212393 (3 mg kg(-1), i.p.)-induced phase advance was antagonized by J-113397 (10 mg kg(-1), i.p.).W-212393 (3 mg kg(-1), i.p.) significantly accelerated the re-entrainment of the body temperature rhythm to a 6 h advanced light-dark cycle. These results indicate that activation of ORL1 receptors contributes to the circadian entrainment and W-212393 may represent an interesting agent for the study of circadian rhythms.
Teshima
Koji
K
Research Laboratory I (CNS), Pharmaceutical Research Unit, R&D Division, Mitsubishi Pharma Corporation, Koyata, Iruma, Saitama, Japan. Teshima.Koji@mk.m-pharma.co.jp
Minoguchi
Masanori
M
Tounai
Sayuri
S
Ashimori
Atsuyuki
A
Eguchi
Junichi
J
Allen
Charles N
CN
Shibata
Shigenobu
S
D000073:Acenaphthenes / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects*; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002940:Circadian Rhythm / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009292:Narcotic Antagonists; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000502:physiology; D000094942:Nociceptin Receptor
C505961:2-(3-(1-(acenaphthen-1-yl)piperidin-4-yl)-2,3-dihydro-2-oxobenzimidazol-1-yl)-N-methylacetamide; D000073:Acenaphthenes; D001562:Benzimidazoles; C402921:J 113397; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor