Characterization of specific binding of L-762,459, a selective α_1A-adrenoceptor radioligand to rat and human tissues

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• 作者：O'Malley ; Stacey S. ; Chen ; Tsing B. ; Francis ; Barbara E. ; Gibson ; Raymond E. ; Burns ; H. Donald ; et. al.
• 关键词：α ; _1A-Adrenoceptor ; Binding ; Radioligand ; Adrenoceptor ; subtype
• 刊名：European Journal of Pharmacology
• 出版年：1998
• 出版时间：May 8, 1998
• 年：1998
• 卷：348
• 期：2-3
• 页码：287-295
• 全文大小：276 K

文摘

L-762,459 ((±)1-(3-{[5-carbamoyl-2-{2-[(4-hydroxy-3-iodobenzimidoyl)-amino]-ethoxy-methyl}-6-methyl-4-(4-nitrophenyl)-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 α_1A-adrenoceptor subtype antagonists was found to have α_1A-adrenoceptor subtype selectivity (K_i (nM), 1a=1.3, 1b=240, 1d=280). Specific L-762,459 binding was detected in rat cerebral cortex, hippocampus, vas deferens, kidney, heart and prostate tissues known to contain the α_1A-adrenoceptor subtype, but not in tissues known to contain α_1B-adrenoceptor (spleen, liver) and α_1D-adrenoceptor (aorta). Scatchard analysis of L-762,459 binding in rat cerebral cortex and prostate indicated a single binding site with a K_d of 0.7 nM and B_max of 11 (cerebral cortex) and 1 (prostate) pmole/g tissue. Specific and saturable L-762,459 binding was also found in human cerebral cortex, liver, prostate and vas deferens (K_d=0.2–0.4 nM, B_max=0.4–4 pmole/g tissue). The specific binding in rat and human tissues was competed by non-selective α₁-adrenoceptor compounds (K_i values in nM: prazosin (0.14–1.2), terazosin (1.8–5.9) and phentolamine (2.4–11)) and selective α_1A-adrenoceptor compounds [K_i values in nM: (+) niguldipine (0.04–1.2) and SNAP 5399 ((±)-2-((2-aminoethyl)oxy)methyl-5-carboxamido-6-ethyl-4-(4-nitrophenyl)-3-N-(3-(4,4-diphenylpiperidin-1-yl)propyl)carboxamido-1,4-dihydropyridine hydrate (0.5–4.8)]. The results were consistent with the selective binding of L-762,459 to the α_1A-adrenoceptor. The specific labeling of the α_1A-adrenoceptor subtype by L-762,459 may make it a useful tool to localize the distribution of the α_1A-adrenoceptor.