title: Characterization of [3H]desmethylimipramine binding in bovine adrenal medulla: interactions with sigma- and (or) phencyclidine-receptor ligands.
abstract: High-affinity binding sites (apparent KD 2.87 nM) for [3H]desmethylimipramine ([3H]DMI), have been demonstrated and characterized in membrane preparations of bovine adrenal medulla. The binding of [3H]DMI improved upon pretreatment of the membrane with KCl and was saturable, sodium dependent, and potently inhibited by nisoxetine and imipramine. [3H]DMI binding was also inhibited by various phencyclidine (PCP)- and (or) sigma-receptor ligands, with the following order of potency: haloperidol > rimcazole > (-)-butaclamol > dextromethorphan > MK-801 > (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) > PCP > N-(2-thienyl)cyclohexyl-3,4-piperidine (TCP) > (+)-SKF-10047 > (-)-SKF-10047. The inhibition produced by sigma ligands was not attributed to stimulation of either sigma 1- or sigma 2-receptors, owing to inactivity of the selective sigma-receptor ligands (+)-pentazocine and 1,3-di(2-tolyl)guanidine (DTG). The inhibition of [3H]DMI binding by sigma- and PCP-receptor ligands was not attributed to PCP1- or PCP2-receptor stimulation, owing to the decreased potency (100-fold) of these ligands in [3H]DMI assays compared with the affinity for brain PCP1 sites, and the ineffectiveness of the PCP2-ligand N-(1-(2-benzo(b)thiophenyl)cyclohexyl)piperidine (BTCP). Scatchard analysis of the inhibition by the sigma-ligands haloperidol and (+)-3-PPP, as well as the PCP1 receptor ligand MK-801, demonstrated noncompetitive interaction with the site bound by [3H]DMI. These studies indicate that bovine adrenomedullary membranes possess a specific receptor for the noradrenaline uptake inhibitor [3H]DMI, which is sensitive to allosteric modulation produced by PCP and sigma-ligands.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ont., Canada.
authors.forename: C
authors.initials: C
authors.lastname: Rogers
authors.forename: S
authors.initials: S
authors.lastname: Lemaire
mesh_terms: D000313:Adrenal Medulla / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002417:Cattle; D003891:Desipramine / Q000378:metabolism*; D003915:Dextromethorphan / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology / Q000031:analogs & derivatives; D010880:Piperidines; D011189:Potassium Chloride / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017478:Receptors, Phencyclidine / Q000378:metabolism*; D014149:Tranquilizing Agents / Q000494:pharmacology
chemical_list: D010880:Piperidines; D017465:Receptors, Opioid, delta; D017478:Receptors, Phencyclidine; D014149:Tranquilizing Agents; D011189:Potassium Chloride; D016291:Dizocilpine Maleate; D003915:Dextromethorphan; C012134:SK&F 10047; C012058:tenocyclidine; C026539:preclamol; D010620:Phenazocine; D010622:Phencyclidine; D003891:Desipramine