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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >Functional selectivity of dopamine receptor agonists.II.actions of dihydrexidine in D_(2L) receptor-transfected MN9D cells and pituitary lactotrophs
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Functional selectivity of dopamine receptor agonists.II.actions of dihydrexidine in D_(2L) receptor-transfected MN9D cells and pituitary lactotrophs

机译：多巴胺受体激动剂的功能选择性II。二氢己定在D_（2L）受体转染的MN9D细胞和垂体乳营养生物中的作用

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摘要

D_2-like dopamine receptors mediate functional changes via activation of inhibitory G proteins,including those that affect adenylate cyclase activity,and potassium and calcium channels.Although it is assumed that the binding of a drug to a single isoform of a D_2-like receptor will cause similar changes in allreceptor-mediated functions,it has been demonstrated in brainthat the dopamine agonists dihydrexidine (DHX) and N-n-propyl-HX are "functionally selective".The current study explores the underlying mechanism using transfected MN9D cells and D-2-producing anterior pituitary lactotrophs.Bothdopamine and DHX inhibited adenylate cyclase activity in a concentration-dependent manner in both systems,effects blocked by D_2,but not D_1,antagonists.In the MN9D cells,quinipirole and R-(-)-N-propylnorapomorphine(NPA) also inhibited the K~+-stimulated release of [~3H]dopamine in a concentration-responsive,antagonist-reversible manner.Conversely,neither DHX,nor its analogs,inhibited K~+-stimulated [~3H]-stimulated [~3H]dopamine release,although they antagonized the effects of quinpirole.S-(+)-NPA actually had the reverse functional selectivity profile from DHX had little intrinsic activity at D_2 receptors coupled to G protein-coupled inwardly rectifying potassium channels,and actually antagonized the effects of dopamine at these D_2 receptors.Together,these findings provide compelling evidence foragonist-induced functional selectivity with the D_(2L) receptor.Although the underlying molecular mechanismis controversial,such data are irreconcil able with the widely held view that drugs hae 'intrinsic efficacy".
机译：D_2样多巴胺受体通过抑制性G蛋白（包括影响腺苷酸环化酶活性以及钾和钙通道的蛋白）的激活来介导功能变化。尽管假定药物与D_2样受体的单一同工型结合引起所有受体介导的功能发生类似的变化，脑中已证明多巴胺激动剂二氢己定（DHX）和Nn-propyl-HX具有“功能选择性”。本研究探索了使用转染的MN9D细胞和D-2-在两个系统中，Bothdopamine和DHX均以浓度依赖的方式抑制腺苷酸环化酶的活性，其作用被D_2拮抗，但未被D_1拮抗。在MN9D细胞中，奎尼吡咯和R-（-）-N-丙基诺rapomorphine（ NPA）还以浓度响应，拮抗剂可逆的方式抑制K〜+刺激的[〜3H]多巴胺释放。相反，DHX及其类似物均不抑制K〜+刺激。 ed [〜3H]刺激的[〜3H]多巴胺释放，尽管它​​们拮抗了喹吡罗的作用。S-（+）-NPA实际上具有与DHX相反的功能选择性，在与G蛋白偶联的D_2受体上几乎没有内在活性。耦合向内整流的钾通道，并实际上拮抗多巴胺对这些D_2受体的作用。这些发现共同为激动剂诱导的D_（2L）受体的功能选择性提供了令人信服的证据。尽管潜在的分子机制尚存争议，但这些数据是不可调和的人们普遍认为药物具有“内在功效”。

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