RS-17053 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

Norepinephrine (NE) contracts smooth muscle cells within the human low er 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 chloro-alp ha,alpha-dimethyl-1H-indole-3-ethanamine hydrochloride (RS-17053) and examine critically the pharmacological identity of the alpha(1)-adreno ceptor mediating contractions to NE in human LUT tissues. In several t issues from rat and cloned adrenoceptors, RS-17053 displayed high affi nity for the alpha(1A)-adrenoceptor (pK(i) and pA(2) estimates of 9.1- 9.9) and a 30-100-fold selectivity over the alpha(1B)- and the alpha(1 D)-adrenoceptor subtypes (pK(i) and pA(2) estimates of 7.7-7.8). Howev er, in isolated smooth muscle preparations from human LUT tissues, RS- 17053 antagonized responses to NE only at high concentrations. Estimat es of affinity (pA(2)) at alpha(1)-adrenoceptors mediating NE-induced contractions were 7.5 in prostatic periurethral longitudinal smooth mu scle (compared with 8.6 for prazosin), 6.9 in anterior fibromuscular s troma (prazosin, 8.9), and 7.1 in bladder neck (prazosin, 8.5). These findings indicate that contractile responses to NE in human LUT tissue s are mediated by a receptor displaying pharmacological properties tha t are clearly different from those of the defined alpha(1A)-adrenocept or ii and raise the possibility that multiple forms of the alpha(1A)-a drenoceptor may exist in human LUT that are discriminated by RS-17053. In this regard, the affinity estimates obtained with RS-17053 and oth er alpha(1)-adrenoceptor antagonists in human LUT tissues are identica l to those described for the putative alpha(1L)-adrenoceptor.