Linked Life Data

10633042

Source:http://linkedlifedata.com/resource/pubmed/id/10633042

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2000-2-14
pubmed:abstractText
This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of kappa agonists related to the morphinan (-)-cyclorphan (3a) and the benzomorphan (-)-cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N-cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)-mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for mu, delta, and kappa opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the kappa receptor than for the mu receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. These findings were confirmed in the antinociceptive tests (tail-flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the delta receptor while 3b did not produce agonist or antagonist effects at the delta receptor. Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
13
pubmed:volume
43
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
114-22
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:10633042-Acetic Acid, pubmed-meshheading:10633042-Animals, pubmed-meshheading:10633042-Benzomorphans, pubmed-meshheading:10633042-Brain, pubmed-meshheading:10633042-Dose-Response Relationship, Drug, pubmed-meshheading:10633042-Ethylketocyclazocine, pubmed-meshheading:10633042-Guinea Pigs, pubmed-meshheading:10633042-Injections, Intraventricular, pubmed-meshheading:10633042-Male, pubmed-meshheading:10633042-Mice, pubmed-meshheading:10633042-Mice, Inbred ICR, pubmed-meshheading:10633042-Morphinans, pubmed-meshheading:10633042-Morphine, pubmed-meshheading:10633042-Narcotic Antagonists, pubmed-meshheading:10633042-Pain, pubmed-meshheading:10633042-Pain Measurement, pubmed-meshheading:10633042-Reaction Time, pubmed-meshheading:10633042-Receptors, Opioid, kappa, pubmed-meshheading:10633042-Receptors, Opioid, mu
pubmed:year
2000
pubmed:articleTitle
Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives: mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine dependence.
pubmed:affiliation
Department of Psychiatry, Harvard Medical School, McLean Hospital, Alcohol and Drug Abuse Research Center, Belmont, Massachusetts 02478-9106, USA. neumeyer@mclean.harvard.edu
pubmed:publicationType
Journal Article, In Vitro, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't