title: Pharmacological characterization of the binding of [3H]bremazocine in guinea-pig brain: evidence for multiplicity of the kappa-opioid receptors.
abstract: In guinea-pig brain, [3H]bremazocine has a binding capacity of 27.2 pmol/g wet tissue, which is statistically different from that of [3H]ethylketazocine (14.7 pmol/g wet tissue) or the sum of the individual binding capacities of mu-, delta-, and kappa-selective ligands (15.0 pmol/g wet tissue). Saturation studies of [3H]bremazocine performed in the presence of unlabelled mu-, delta-, and kappa-blockers still reveal a homogeneous population of binding sites. [3H]Bremazocine under suppressed conditions displays at these sites a Kd of 2.51 nM with a binding capacity of 9.15 pmol/g wet tissue. We have performed the pharmacological characterization of these additional opioid binding sites. Displacement curves measured with a number of opioid substances were all best fitted to a one-site model. The stereoselectivity of these additional sites was demonstrated by using two groups of stereoisomers. Oripavine and benzomorphan opioids were among the most potent drugs at the [3H]bremazocine sites (mu + delta + kappa suppressed). Diprenorphine, bremazocine, cyclazocine, and ethylketazocine displayed apparent affinities constants (1/Ka) of 8.66, 7.57, 21.4, and 38.0 nM, respectively at those sites. The kappa-selective drugs U50488, U69593, PD117302, and tifluadom were inhibitors of the binding of [3H]bremazocine at these sites with apparent affinities of 113, 268, 76.9, and 47.9 nM. All mu- or delta-selective drugs tested in this study have caused weak or no inhibition of the binding. Correlation analyses were done between the different affinities measured at the [3H]bremazocine sites (mu + delta + kappa suppressed) and those observed at the known mu-, delta-, and kappa-sites of the guinea-pig brain.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Département de Pharmacologie, Université de Montréal, (Québec), Canada.
authors.forename: M
authors.initials: M
authors.lastname: Tiberi
authors.forename: J
authors.initials: J
authors.lastname: Magnan
mesh_terms: D000818:Animals; D001575:Benzomorphans / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000378:metabolism; D016314:Ethylketocyclazocine; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008566:Membranes / Q000378:metabolism; D008954:Models, Biological; D009019:Morphinans / Q000378:metabolism*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013237:Stereoisomerism
chemical_list: D001575:Benzomorphans; D009019:Morphinans; D010455:Peptides; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D016314:Ethylketocyclazocine; C027248:bremazocine; D003496:Cyclazocine