| Autor: |
Teshima, Koji, Minoguchi, Masanori, Tounai, Sayuri, Ashimori, Atsuyuki, Eguchi, Junichi, Allen, Charles N., Shibata, Shigenobu |
| Předmět: |
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| Zdroj: |
British Journal of Pharmacology; Sep2005, Vol. 146 Issue 1, p33-40, 8p |
| Abstrakt: |
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 Ki values of 0.76 and 0.50 nM, respectively.W-212393 concentration-dependently stimulated GTPγ35S 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 μM).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.British Journal of Pharmacology (2005) 146, 33–40. doi:10.1038/sj.bjp.0706311; published online 27 June 2005 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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