title: Characterization of specific binding of [125I]L-762,459, a selective alpha1A-adrenoceptor radioligand to rat and human tissues.
abstract: 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.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: O'Malley
authors.forename: T B
authors.initials: TB
authors.lastname: Chen
authors.forename: B E
authors.initials: BE
authors.lastname: Francis
authors.forename: R E
authors.initials: RE
authors.lastname: Gibson
authors.forename: H D
authors.initials: HD
authors.lastname: Burns
authors.forename: J
authors.initials: J
authors.lastname: DiSalvo
authors.forename: M L
authors.initials: ML
authors.lastname: Bayne
authors.forename: J M
authors.initials: JM
authors.lastname: Wetzel
authors.forename: D
authors.initials: D
authors.lastname: Nagarathnam
authors.forename: M
authors.initials: M
authors.lastname: Marzabadi
authors.forename: C
authors.initials: C
authors.lastname: Gluchowski
authors.forename: R S
authors.initials: RS
authors.lastname: Chang
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism*; D000578:Amidines / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D004095:Dihydropyridines / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D007668:Kidney / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010646:Phentolamine / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism; D011224:Prazosin / Q000031:analogs & derivatives / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000378:metabolism
chemical_list: C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000578:Amidines; D004095:Dihydropyridines; D007457:Iodine Radioisotopes; C114931:L 762459; D010880:Piperidines; D018340:Receptors, Adrenergic, alpha-1; C097131:SNAP 5272; C041226:Terazosin; D011224:Prazosin; D010646:Phentolamine