Document Detail


N-cyclobutylmethyl analog of normorphinone, N-CBM-TAMO: a short-term opioid agonist and long-term Mu-selective irreversible opioid antagonist.
MedLine Citation:
PMID:  8930155     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The antinociceptive and opioid binding properties of the N-cyclobutylmethyl analog of normorphinone, 14 alpha, 14' beta-[dithiobis[(2-oxo-2, 1-ethanediyl)imino]]bis[7,8-dihydro-N-(cyclobutylmethyl)-normor phinone] (N-CBM-TAMO) were investigated. This compound is a dimer, containing a disulfide capable of binding to thiol groups on the opioid receptor. Competition radioligand binding assays with bovine striatal membranes demonstrated that N-CBM-TAMO displayed a higher affinity for mu opioid receptors than for kappa and delta receptors. Incubation of membranes with N-CBM-TAMO resulted in wash-resistant inhibition of the binding of the mu-selective peptide [3H][D-Ala2,(Me)Phe4, Gly(ol)5]-enkephalin, the kappa-selective opioid [3H]U69,593 ((trans)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide+ ++ methanesulfonate hydrate)) and, to a lesser extent, the delta-selective peptide [D-Pen2, p-Cl-phenylalanine4, D-Pen5]enkephalin. Scatchard analysis of saturation binding data showed that N-CBM-TAMO decreased the Bmax value without affecting the Kd value for [3H][D-Ala2,(Me)Phe4, Gly(ol)5]enkephalin binding, whereas, N-CBM-TAMO increased the Kd value without altering the Bmax value for [3H]U69,593, which suggests that N-CBM-TAMO interacted covalently with the mu but not the kappa receptor. In the mouse 55 degrees C warm-water tail-flick test, N-CBM-TAMO given supraspinally acted as an agonist with low efficacy because only submaximal antinociception was observed at doses up to 100 nmol. The antinociception induced by N-CBM-TAMO in the tail-flick test was partially blocked by both the mu-selective antagonist beta-funaltrexamine and the kappa-selective antagonist nor-binaltorphimine. In the mouse acetic acid writhing test, N-CBM-TAMO acted as a full agonist with a D50 value of 0.08 (0.04-0.14) nmol, and the antinociception was blocked by coadministration of the kappa-selective antagonist nor-binaltorphimine. Pretreatment of mice with an i.c.v. dose of N-CBM-TAMO of 10 nmol, a dose that exhibited modest short-term antinociception in the tail-flick test, produced a time- and dose-dependent long-term antagonism of morphine-induced antinociception in an irreversible manner in this assay. Pretreatment of mice with i.c.v. N-CBM-TAMO at doses of 3 nmol and higher, which produced supermaximal short-term antinociception in the writhing test, produced a time- and dose-dependent long-term antagonism of U50,488 (trans)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate hydrate)-induced antinociception in a reversible manner, probably because of the development of tolerance. These in vivo data, together with the in vitro binding data, demonstrate that N-CBM-TAMO is a potent kappa agonist and at higher doses produces antinociception mediated by mu receptors. N-CBM-TAMO also produces long-term noncompetitive antagonism of antinociception mediated by mu opioid receptors.
Authors:
J Y Xu; A Seyed-Mozaffari; S Archer; J M Bidlack
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  279     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1996 Nov 
Date Detail:
Created Date:  1996-12-24     Completed Date:  1996-12-24     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  539-47     Citation Subset:  IM    
Affiliation:
Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, New York, USA.
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MeSH Terms
Descriptor/Qualifier:
Analgesics, Opioid / pharmacology*
Animals
Benzeneacetamides*
Cattle
Dose-Response Relationship, Drug
Hydromorphone / analogs & derivatives*,  pharmacology
Male
Mice
Mice, Inbred ICR
Morphine / antagonists & inhibitors
Narcotic Antagonists / pharmacology*
Opioid-Related Disorders / drug therapy
Pyrrolidines / pharmacology
Receptors, Opioid, mu / antagonists & inhibitors*
Grant Support
ID/Acronym/Agency:
DA01674/DA/NIDA NIH HHS; DA03742/DA/NIDA NIH HHS; DA07232/DA/NIDA NIH HHS
Chemical
Reg. No./Substance:
0/14,14'-(dithio-bis((2-oxo-2,1-ethanediyl)imino))bis(7,8-dihydro-N-(cyclobutylmethyl)normophinone); 0/Analgesics, Opioid; 0/Benzeneacetamides; 0/Narcotic Antagonists; 0/Pyrrolidines; 0/Receptors, Opioid, mu; 466-99-9/Hydromorphone; 57-27-2/Morphine; 96744-75-1/U 69593

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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