Rogers C, Lemaire S
Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ont., Canada.
Can J Physiol Pharmacol. 1992 Nov;70(11):1508-14. doi: 10.1139/y92-214.
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.
已在牛肾上腺髓质的膜制剂中证实并表征了[3H]去甲丙咪嗪（[3H]DMI）的高亲和力结合位点（表观解离常数KD为2.87 nM）。用氯化钾预处理膜后，[3H]DMI的结合得到改善，且具有饱和性、钠依赖性，并被尼索西汀和丙咪嗪强烈抑制。[3H]DMI结合也受到各种苯环利定（PCP）和（或）西格玛受体配体的抑制，其效力顺序如下：氟哌啶醇＞利米唑＞（-）-布他拉莫＞右美沙芬＞MK-801＞（+）-3-（3-羟苯基）-N-（1-丙基）哌啶（（+）-3-PPP）＞PCP＞N-（2-噻吩基）环己基-3,4-哌啶（TCP）＞（+）-SKF-10047＞（-）-SKF-10047。由于选择性西格玛受体配体（+）-喷他佐辛和1,3-二（2-甲苯基）胍（DTG）无活性，西格玛配体产生的抑制作用并非归因于对西格玛1或西格玛2受体的刺激。西格玛和PCP受体配体对[3H]DMI结合的抑制作用并非归因于对PCP1或PCP2受体的刺激，因为与对脑PCP1位点的亲和力相比，这些配体在[3H]DMI测定中的效力降低了（100倍），且PCP2配体N-（1-（2-苯并（b）噻吩基）环己基）哌啶（BTCP）无效。对西格玛配体氟哌啶醇和（+）-3-PPP以及PCP1受体配体MK-801的抑制作用进行的斯卡查德分析表明，它们与[3H]DMI结合的位点存在非竞争性相互作用。这些研究表明，牛肾上腺髓质膜具有去甲肾上腺素摄取抑制剂[3H]DMI的特异性受体，该受体对PCP和西格玛配体产生的变构调节敏感。
