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Pharmacological characterization of AR-M1000390 at human delta opioid receptors.
- Source :
-
Life sciences [Life Sci] 2003 Aug 15; Vol. 73 (13), pp. 1691-704. - Publication Year :
- 2003
-
Abstract
- We investigated the pharmacological properties of a newly synthesised delta agonist AR-M1000390, derived from SNC-80 ((+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethyl-benzamide), in the neuroblastoma cell line SK-N-BE expressing only human delta-opioid receptors. Binding and functional experiments showed a weak affinity (K(i) = 106 +/- 34 nM) correlated with a weak potency (EC(50) = 111 +/- 31 nM) to inhibit the forskolin-stimulated cAMP accumulation. Sustained activation of opioid receptors in the presence of the maximal inhibitory concentration of AR-M1000390 produced a rapid and strong desensitization. In order to examine the contribution of internalization and down-regulation in the desensitization processes, binding and functional experiments were conducted in the presence or in the absence of hypertonic sucrose solution to block clathrin-dependent opioid receptor endocytosis. We observed both the inability of AR-M1000390 to down-regulate opioid receptors and the absence of any effect of sucrose on desensitization. The lack of delta-opioid receptor internalization by AR-M1000390 was further corroborated by confocal microscopy using antibodies directed either against the endogenous delta-opioid receptors or the FLAG-tagged delta-opioid receptors stably expressed in the SK-N-BE cells. These data suggest that uncoupling rather than internalization is responsible for delta-opioid receptors desensitization by AR-M1000390.
- Subjects :
- Adenylyl Cyclases metabolism
Down-Regulation
Endocytosis drug effects
Humans
Microscopy, Confocal
Neuroblastoma metabolism
Neuroblastoma pathology
Piperazines
Receptors, Opioid, delta immunology
Receptors, Opioid, delta metabolism
Signal Transduction
Sucrose pharmacology
Tumor Cells, Cultured
Benzamides pharmacology
Narcotic Antagonists pharmacology
Piperidines pharmacology
Receptors, Opioid, delta agonists
Subjects
Details
- Language :
- English
- ISSN :
- 0024-3205
- Volume :
- 73
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Life sciences
- Publication Type :
- Academic Journal
- Accession number :
- 12875901
- Full Text :
- https://doi.org/10.1016/s0024-3205(03)00489-2