Bylund D B, Ray-Prenger C, Murphy T J
Department of Pharmacology, School of Medicine, University of Missouri, Columbia.
J Pharmacol Exp Ther. 1988 May;245(2):600-7.
The affinities of 34 adrenergic antagonists for alpha-2 adrenergic receptors were determined from homogenate radioligand binding studies using [3H]yohimbine and [3H]rauwolscine. It has been suggested that alpha-2 adrenergic receptors can be subdivided into alpha-2A and alpha-2B subtypes. Oxymetazoline is selective for alpha-2A receptors, whereas prazosin is alpha-2B selective. Five different tissues were used, each of which has only one of the two subtypes: human platelet (alpha-2A), HT29 cell line (alpha-2A), human cerebral cortex (alpha-2A), neonatal rat lung (alpha-2B), and NG108-15 cell line (alpha-2B). The drug affinities were highly correlated when alpha-2A tissues were compared with alpha-2A tissues (r = 0.97 to 0.98) or when the two alpha-2B tissues were compared (r = 0.99). By contrast, comparison of an alpha-2A tissue with an alpha-2B tissue resulted in poor correlations (r = 0.77 to -0.87). Three new subtype selective drugs were identified among these drugs on the basis of at least a 10-fold greater affinity for one subtype. All three were selective for the alpha-2B subtype: ARC-239 (100-fold selective), chlorpromazine (18-fold selective), and 7-hydroxychlorpromazine (17-fold selective). These studies, by demonstrating distinct pharmacological profiles for the two alpha-2 adrenergic receptor subtypes in several different tissues, further support the existence and definition of these subtypes. The identification of a cell line for each subtype should be useful in the further study of alpha-2 adrenergic receptor subtypes.
利用[3H]育亨宾和[3H]萝芙木碱，通过匀浆放射性配体结合研究确定了34种肾上腺素能拮抗剂对α-2肾上腺素能受体的亲和力。有人提出α-2肾上腺素能受体可细分为α-2A和α-2B亚型。羟甲唑啉对α-2A受体具有选择性，而哌唑嗪对α-2B受体具有选择性。使用了五种不同的组织，每种组织仅具有两种亚型之一：人血小板（α-2A）、HT29细胞系（α-2A）、人大脑皮层（α-2A）、新生大鼠肺（α-2B）和NG108-15细胞系（α-2B）。当α-2A组织与α-2A组织比较时（r = 0.97至0.98）或当两种α-2B组织比较时（r = 0.99），药物亲和力高度相关。相比之下，α-2A组织与α-2B组织的比较相关性较差（r = 0.77至-0.87）。在这些药物中，基于对一种亚型的亲和力至少高10倍，鉴定出了三种新的亚型选择性药物。所有三种药物均对α-2B亚型具有选择性：ARC-239（100倍选择性）、氯丙嗪（18倍选择性）和7-羟基氯丙嗪（17倍选择性）。这些研究通过在几种不同组织中证明两种α-2肾上腺素能受体亚型具有不同的药理学特征，进一步支持了这些亚型存在和定义。为每种亚型鉴定细胞系应有助于进一步研究α-2肾上腺素能受体亚型。
