Sloan J W, Martin W R, Bostwick M, Hook R, Wala E
University of Kentucky, College of Medicine, Department of Pharmacology, Lexington 40536.
Pharmacol Biochem Behav. 1988 May;30(1):255-67. doi: 10.1016/0091-3057(88)90454-6.
Five drugs [(-)- and (+)-nicotine, (-)-lobeline, (-)-anabasine and (-)-cytisine] were infused IV into the urethane-pentobarbital anesthetized rat. Changes in heart rate, blood pressure, respiratory rate, minute and tidal volume, which appeared to be largely centrally mediated, were studied. Each of these compounds produced different pharmacologic profiles. The nature of these dissimilarities is not readily explained on the basis of pharmacokinetic considerations suggesting that the drugs have different mechanisms of action. Binding data obtained with these compounds using the rat brain P2 preparation also show differences. (-)-Lobeline and (-)-anabasine, like the nicotinic antagonists mecamylamine and hexamethonium, bind predominantly to low affinity sites with KDs in the micromolar range whereas (-)-cytisine binds only to a single high affinity site with a KD in the nanomolar range. Further, the binding patterns of these drugs are different from (-)- and (+)-nicotine which bind to both high and low affinity sites but differ from each other in binding characteristics. Thus the binding data are consistent with the pharmacologic data in suggesting that the drugs have different modes of action and support the concept that the low affinity site has an important role in the central nervous system action of these compounds.
将五种药物[(-)-和(+)-尼古丁、(-)-洛贝林、(-)-新烟草碱和(-)-金雀花碱]静脉注射到经氨基甲酸乙酯-戊巴比妥麻醉的大鼠体内。研究了心率、血压、呼吸频率、每分通气量和潮气量的变化，这些变化似乎主要由中枢介导。这些化合物中的每一种都产生了不同的药理学特征。这些差异的性质难以根据药代动力学考虑来解释，这表明这些药物具有不同的作用机制。使用大鼠脑P2制剂获得的这些化合物的结合数据也显示出差异。(-)-洛贝林和(-)-新烟草碱，与烟碱拮抗剂美加明和六甲铵一样，主要与低亲和力位点结合，解离常数在微摩尔范围内，而(-)-金雀花碱仅与单个高亲和力位点结合，解离常数在纳摩尔范围内。此外，这些药物的结合模式与(-)-和(+)-尼古丁不同，(-)-和(+)-尼古丁与高亲和力和低亲和力位点都结合，但在结合特性上彼此不同。因此，结合数据与药理学数据一致，表明这些药物具有不同的作用模式，并支持低亲和力位点在这些化合物的中枢神经系统作用中起重要作用的概念。
