Kusayama T, Oka J, Yabana H, Adachi-Akahane S, Nagao T
Department of Toxicology and Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Biol Pharm Bull. 1994 Aug;17(8):1023-7. doi: 10.1248/bpb.17.1023.
The affinities for beta-adrenoceptors, the subtype-selectivity and the agonistic effectiveness of T-0509 (a catechol derivative of denopamine) and colterol (N-tert-butylnoradrenaline; Col) were compared with those of other beta-agonists using a binding assay method. Specific binding of [3H]dihydroalprenolol (3H-DHA) to guinea pig left ventricular and lung membranes was saturable, and Scatchard and Hill analyses suggested that 3H-DHA bound to both membranes with a single population of binding sites with no binding site cooperativity. Addition of 5'-guanylylimidodiphosphate (GppNHp, 30 microM) led to a rightward shift of the 3H-DHA binding displacement curves of T-0509 and Col in both membranes, and the degree of shift was similar to that of full agonists such as isoproterenol (Iso), adrenaline (Adr) and noradrenaline (NA). Both T-0509 and Col were thus considered to be full agonists at both beta 1- and beta 2-adrenoceptors, respectively, unlike denopamine and procaterol. T-0509 and Col showed considerably high affinity for both beta 1- and beta 2-adrenoceptors, and T-0509, like denopamine, was as selective for the beta 1-subtype as NA (4.5-fold compared with Iso as a non-selective agonist), whereas Col was more selective for the beta 2-subtype than Adr (4.5-fold compared with Iso).
采用结合测定法，将T-0509（多巴胺的儿茶酚衍生物）和可多特罗（N-叔丁基去甲肾上腺素；Col）对β-肾上腺素受体的亲和力、亚型选择性和激动效力，与其他β-激动剂进行了比较。[3H]二氢心得舒（3H-DHA）与豚鼠左心室和肺膜的特异性结合具有饱和性，Scatchard和Hill分析表明，3H-DHA与两种膜的结合位点均为单一群体，不存在结合位点协同性。加入5'-鸟苷酰亚胺二磷酸（GppNHp，30μM）导致T-0509和Col在两种膜中的3H-DHA结合置换曲线向右移动，且移动程度与异丙肾上腺素（Iso）、肾上腺素（Adr）和去甲肾上腺素（NA）等完全激动剂相似。因此，与多巴胺和丙卡特罗不同，T-0509和Col分别被认为是β1-和β2-肾上腺素受体的完全激动剂。T-0509和Col对β1-和β2-肾上腺素受体均表现出相当高的亲和力，并且T-0509与多巴胺一样，对β1-亚型的选择性与NA相同（与非选择性激动剂Iso相比为4.5倍），而Col对β2-亚型的选择性高于Adr（与Iso相比为4.5倍）。
