Switch to
Predicate | Object |
---|---|
rdf:type | |
lifeskim:mentions | |
pubmed:issue |
2
|
pubmed:dateCreated |
1996-12-24
|
pubmed:abstractText |
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.
|
pubmed:grant | |
pubmed:language |
eng
|
pubmed:journal | |
pubmed:citationSubset |
IM
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Analgesics, Opioid,
http://linkedlifedata.com/resource/pubmed/chemical/Benzeneacetamides,
http://linkedlifedata.com/resource/pubmed/chemical/Hydromorphone,
http://linkedlifedata.com/resource/pubmed/chemical/Morphine,
http://linkedlifedata.com/resource/pubmed/chemical/Narcotic Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrrolidines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Opioid, mu,
http://linkedlifedata.com/resource/pubmed/chemical/U 69593
|
pubmed:status |
MEDLINE
|
pubmed:month |
Nov
|
pubmed:issn |
0022-3565
|
pubmed:author | |
pubmed:issnType |
Print
|
pubmed:volume |
279
|
pubmed:owner |
NLM
|
pubmed:authorsComplete |
Y
|
pubmed:pagination |
539-47
|
pubmed:dateRevised |
2007-11-14
|
pubmed:meshHeading |
pubmed-meshheading:8930155-Analgesics, Opioid,
pubmed-meshheading:8930155-Animals,
pubmed-meshheading:8930155-Benzeneacetamides,
pubmed-meshheading:8930155-Cattle,
pubmed-meshheading:8930155-Dose-Response Relationship, Drug,
pubmed-meshheading:8930155-Hydromorphone,
pubmed-meshheading:8930155-Male,
pubmed-meshheading:8930155-Mice,
pubmed-meshheading:8930155-Mice, Inbred ICR,
pubmed-meshheading:8930155-Morphine,
pubmed-meshheading:8930155-Narcotic Antagonists,
pubmed-meshheading:8930155-Opioid-Related Disorders,
pubmed-meshheading:8930155-Pyrrolidines,
pubmed-meshheading:8930155-Receptors, Opioid, mu
|
pubmed:year |
1996
|
pubmed:articleTitle |
N-cyclobutylmethyl analog of normorphinone, N-CBM-TAMO: a short-term opioid agonist and long-term Mu-selective irreversible opioid antagonist.
|
pubmed:affiliation |
Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, New York, USA.
|
pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
|