title: RS-17053 (N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha, alpha-dimethyl-1H-indole-3-ethanamine hydrochloride), a selective alpha 1A-adrenoceptor antagonist, displays low affinity for functional alpha 1-adrenoceptors in human prostate: implications for adrenoceptor classification.
abstract: Norepinephrine (NE) contracts smooth muscle cells within the human lower urinary tract (LUT) (bladder neck, prostate, and urethra). Receptor distribution and pharmacological evidence have implicated activation of alpha 1A-adrenoceptors. We disclose the pharmacological properties of the novel, selective alpha 1A-adrenoceptor antagonist N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro- alpha,alpha-dimethyl-1H-indole-3-ethanamine hydrochloride (RS-17053) and examine critically the pharmacological identity of the alpha 1-adrenoceptor mediating contractions to NE in human LUT tissues. In several tissues from rat and cloned adrenoceptors, RS-17053 displayed high affinity for the alpha 1A-adrenoceptor (pKi and pA2 estimates of 9.1-9.9) and a 30-100-fold selectivity over the alpha 1B- and the alpha 1D-adrenoceptor subtypes (pK1 and pA2 estimates of 7.7-7.8). However, in isolated smooth muscle preparations from human LUT tissues, RS-17053 antagonized responses to NE only at high concentrations. Estimates of affinity (pA2) at alpha 1-adrenoceptors mediating NE-induced contractions were 7.5 in prostatic periurethral longitudinal smooth muscle (compared with 8.6 for prazosin), 6.9 in anterior fibromuscular stroma (prazosin, 8.9), and 7.1 in bladder neck (prazosin, 8.5). These findings indicate that contractile responses to NE in human LUT tissues are mediated by a receptor displaying pharmacological properties that are clearly different from those of the defined alpha 1A-adrenoceptor and raise the possibility that multiple forms of the alpha 1A-adrenoceptor may exist in human LUT that are discriminated by RS-17053. In this regard, the affinity estimates obtained with RS-17053 and other alpha 1-adrenoceptor antagonists in human LUT tissues are identical to those described for the putative alpha 1L-adrenoceptor.
authors.affiliation: Center for Neurobiology, Roche Bioscience, Palo Alto, California, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Ford
authors.forename: N F
authors.initials: NF
authors.lastname: Arredondo
authors.forename: D R
authors.initials: DR
authors.lastname: Blue
authors.forename: D W
authors.initials: DW
authors.lastname: Bonhaus
authors.forename: J
authors.initials: J
authors.lastname: Jasper
authors.forename: M S
authors.initials: MS
authors.lastname: Kava
authors.forename: J
authors.initials: J
authors.lastname: Lesnick
authors.forename: J R
authors.initials: JR
authors.lastname: Pfister
authors.forename: I A
authors.initials: IA
authors.lastname: Shieh
authors.forename: R L
authors.initials: RL
authors.lastname: Vimont
authors.forename: T J
authors.initials: TJ
authors.lastname: Williams
authors.forename: J E
authors.initials: JE
authors.lastname: McNeal
authors.forename: T A
authors.initials: TA
authors.lastname: Stamey
authors.forename: D E
authors.initials: DE
authors.lastname: Clarke
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D006224:Cricetinae; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000502:physiology*; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000145:classification / Q000378:metabolism* / Q000502:physiology; D014551:Urinary Tract / Q000187:drug effects; D014553:Urinary Tract Physiological Phenomena
chemical_list: D000317:Adrenergic alpha-Antagonists; D007211:Indoles; C099495:RS 17053; D018340:Receptors, Adrenergic, alpha-1; D009638:Norepinephrine