An in vitro profile of activity for the (+) and (-) enantiomers of spiradoline and PD117302.
Kappa- and mu-opioid binding site affinities of the kappa-selective ligand U62066 and its optical isomers, (+)-U63639 and (-)-U63640 were compared with those of the structurally related ligand PD117302 and its respective isomers, (+)-PD123497 and (-)-PD123475. The relative efficacies of each compound were also established using the guinea-pig ileum, rat and rabbit vas deferens smooth muscle bioassays. The specific opioid receptor mediating the agonist behaviour was determined in the guinea-pig ileum bioassay by obtaining pKB values for naloxone and for the kappa-selective antagonist nor-binaltorphimine. Both racemic compounds and the (-)-enantiomers displayed high selectivity for the kappa-receptor with (-)-PD123475 the most selective. The (+)-enantiomer, PD123497, was approximately equipotent at mu-/kappa-sites while (+)-U63639 displayed a 140-fold mu-receptor selectivity. Bioassay studies showed each compound to be interacting at the kappa-receptor, with the exception of (+)-U63639 which displayed a profile consistent with that of a weak mu-receptor agonist.
Meecham
K G
KG
Parke Davis Research Unit, New Addenbrookes Hospital Site, Cambridge, U.K.
Boyle
S J
SJ
Hunter
J C
JC
Hughes
J
J
D000818:Animals; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013237:Stereoisomerism; D013876:Thiophenes / Q000494:pharmacology*; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
D011758:Pyrroles; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013876:Thiophenes; C054718:PD 117302; C051272:spiradoline