O'Malley S S, Chen T B, Francis B E, Gibson R E, Burns H D, DiSalvo J, Bayne M L, Wetzel J M, Nagarathnam D, Marzabadi M, Gluchowski C, Chang R S
Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
Eur J Pharmacol. 1998 May 8;348(2-3):287-95. doi: 10.1016/s0014-2999(98)00149-6.
L-762,459 ((+/-)1-(3-¿[5-carbamoyl-2-2-[(4-hydroxy-3-iodobenzimidoyl)-amino] -ethoxy-methy¿-6-methyl-4-(4-nitropheny)-1,4-dihydropyridine -3-carbonyl]-amino¿-propyl)-4-phenyl-1-piperidine-4-carboxylic acid methyl ester), an analog of a series of dihydropyridines previously reported to be selective alpha1A-adrenoceptor subtype antagonists was found to have alpha1A-adrenoceptor subtype selectivity (Ki (nM), la = 1.3, lb = 240, Id = 280). Specific [125I]L-762,459 binding was detected in rat cerebral cortex, hippocampus, vas deferens, kidney, heart and prostate tissues known to contain the alpha1A-adrenoceptor subtype, but not in tissues known to contain alpha1B-adrenoceptor (spleen, liver) and alpha1D-adrenoceptor (aorta). Scatchard analysis of [125I]L-762,459 binding in rat cerebral cortex and prostate indicated a single binding site with a Kd of 0.7 nM and Bmax of 11 (cerebral cortex) and 1 (prostate) pmole/g tissue. Specific and saturable [125I]L-762,459 binding was also found in human cerebral cortex, liver, prostate and vas deferens (Kd = 0.2-0.4 nM, Bmax = 0.4-4 pmole/g tissue). The specific binding in rat and human tissues was competed by non-selective alpha1-adrenoceptor compounds (Ki values in nM: prazosin (0.14-1.2), terazosin (1.8-5.9) and phentolamine (2.4-11)) and selective alpha1A-adrenoceptor compounds [Ki values in nM: (+) niguldipine (0.04-1.2) and SNAP 5399 ((+/-)-2-((2-aminoethyl)oxy)methyl-5-carboxamido-6-ethyl-4-(4-nitropheny l)-3-N-(3-(4,4-diphenylpiperidin-1-yl)propyl)carboxamido-1,4-dihyd ropyridine hydrate (0.5-4.8)]. The results were consistent with the selective binding of [125I]L-762,459 to the alpha1A-adrenoceptor. The specific labeling of the alpha1A-adrenoceptor subtype by [125I]L-762,459 may make it a useful tool to localize the distribution of the alpha1A-adrenoceptor.
L-762,459（（±）1-（3- [5-氨基甲酰基-2- [（4-羟基-3-碘苯甲酰亚氨基）-氨基] -乙氧基-甲基] -6-甲基-4-（4-硝基苯基）-1,4-二氢吡啶-3-羰基] -氨基）-丙基）-4-苯基-1-哌啶-4-羧酸甲酯），是先前报道的一系列二氢吡啶的类似物，被发现具有α1A-肾上腺素能受体亚型选择性（Ki（nM），α1A = 1.3，α1B = 240，α1D = 280）。在已知含有α1A-肾上腺素能受体亚型的大鼠大脑皮层、海马体、输精管、肾脏、心脏和前列腺组织中检测到特异性的[125I]L-762,459结合，但在已知含有α1B-肾上腺素能受体（脾脏、肝脏）和α1D-肾上腺素能受体（主动脉）的组织中未检测到。对大鼠大脑皮层和前列腺中[125I]L-762,459结合的Scatchard分析表明存在单一结合位点，其解离常数（Kd）为0.7 nM，最大结合容量（Bmax）在大脑皮层中为11，在前列腺中为1 pmol/g组织。在人大脑皮层、肝脏、前列腺和输精管中也发现了特异性且可饱和的[125I]L-762,459结合（Kd = 0.2 - 0.4 nM，Bmax = 0.4 - 4 pmol/g组织）。大鼠和人组织中的特异性结合可被非选择性α1-肾上腺素能受体化合物（Ki值，单位为nM：哌唑嗪（0.14 - 1.2）、特拉唑嗪（1.8 - 5.9）和酚妥拉明（2.4 - 11））以及选择性α1A-肾上腺素能受体化合物[Ki值，单位为nM：（+）尼群地平（0.04 - 1.2）和SNAP 5399（（±）-2-（（2-氨基乙基）氧基）甲基-5-羧酰胺基-6-乙基-4-（4-硝基苯基）-3-N-（3-（4,4-二苯基哌啶-1-基）丙基）羧酰胺基-1,4-二氢吡啶水合物（0.5 - 4.8）]竞争。这些结果与[125I]L-762,459对α1A-肾上腺素能受体的选择性结合一致。[125I]L-762,459对α1A-肾上腺素能受体亚型的特异性标记可能使其成为定位α1A-肾上腺素能受体分布的有用工具。
