Characterization Of Specific Binding Of [I-125]L-762,459, A Selective Alpha(1a)-Adrenoceptor Radioligand To Rat And Human Tissues
EUROPEAN JOURNAL OF PHARMACOLOGY(1998)
摘要
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 alpha(1A)-adrenoceptor subtype antagonists was found to have alpha(1A)-adrenoceptor subtype selectivity (K-i (nM), la = 1.3, Ib = 240, Id = 280). Specific [I-125]L-762,459 binding was detected in rat cerebral cortex, hippocampus, vas deferens, kidney, heart and prostate tissues known to contain the alpha(1A)-adrenoceptor subtype, but not in tissues known to contain alpha(1B)-adrenoceptor (spleen, liver) and alpha(1D)-adrenoceptor (aorta). Scatchard analysis of [I-125]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 [I-125]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 alpha(1)-adrenoceptor compounds (K-i values in nM, prazosin (0.14-1.2), terazosin (1.8-5.9) and phentolamine (2.4-11)) and selective alpha(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 [I-125]L-762,459 to the alpha(1A)-adrenoceptor. The specific labeling of the a,, adrenoceptor subtype by [I-125]L-762,459 may make it a useful tool to localize the distribution of the alpha(1A)-adrenoceptor. (C) 1998 Elsevier Science B.V. All rights reserved.
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关键词
alpha(1A)-adrenoceptor, binding, radioligand, adrenoceptor, subtype
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