Comparison of kappa opioids in rhesus monkeys: behavioral effects and receptor binding affinities.
Bremazocine, [5R-(5,7,8 beta)]-N-methyl-N-[7-(1-pyrrolidinyl)1-oxaspiro [4,5]dec-8-yl]-4-benzofuranacetamide (Cl-977), (+-)-trans-3,4-dichloro-N- methyl-(2-(pyrrolidin-1-yl)-5-methoxy-1,2,3,4-tetrahydronapth++ +-1-yl benzeneacetamide methanesulfonate (DUP 747), ethylketocyclazocine (EKC), nalorphine, (+/-)-trans-N-methyl-N-[2-(1- pyrrolidnyl)-cyclohexyl]benzo[b]thiophene-4-acetamide (PD117302), trans-(+/-)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)- cyclohexyl]benzeneacetamide (U-50,488), (5,7,8 beta)-N-methyl-N[2-(1- pyrrolidinyl), 1-oxaspiro[4,5]dec-8-yl benzeneacetamide (U-69,593) and spiradoline were compared in rhesus monkeys for their discriminative stimulus, analgesic and respiratory effects. Selected compounds also were studied for their binding affinities at mu [[3H](D-Ala2-Me-Phe4,Glyol5)enkephalin], kappa ([3H]U-69,593) and delta [[3H](D-Pen2-D-Pen5) enkephalin], opioid receptors in monkey brain membranes. All compounds substituted completely (> or = 90%) for EKC in monkeys discriminating between EKC and saline, with the exception that DUP 747 produced a maximum of 74% EKC responding. None of the compounds reversed naltrexone responding in morphine-abstinent monkeys; all of the compounds substituted for naltrexone in morphine-treated monkeys discriminating between naltrexone and saline, with the exception that spiradoline produced a maximum of 68% naltrexone responding. Eight compounds produced maximum analgesic effects in a tail withdrawal procedure and quadazocine antagonized these effects; nalorphine did not have analgesic effects, but it antagonized analgesic effects of several other compounds. U-50,488 did not decrease respiratory function, whereas U-69,593 decreased frequency of respiration and volume of respiration to less than 40% of control values; Cl-977, DUP 747, PD117302 and spiradoline had limited effects on respiratory function. Larger doses of each compound increased both respiration and motor activity.
France
C P
CP
Department of Pharmacology, Louisiana State University Medical Center, New Orleans.
Medzihradsky
F
F
Woods
J H
JH
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001665:Binding Sites; D016314:Ethylketocyclazocine / Q000494:pharmacology; D005260:Female; D008253:Macaca mulatta; D008297:Male; D015394:Molecular Structure; D009271:Naltrexone / Q000494:pharmacology; D009294:Narcotics / Q000145:classification / Q000378:metabolism / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000378:metabolism; D012119:Respiration / Q000187:drug effects
D000700:Analgesics; D009294:Narcotics; D017473:Receptors, Opioid, kappa; D016314:Ethylketocyclazocine; D009271:Naltrexone