rs-17053 and Prostatic-Hyperplasia

Topics: 5-alpha Reductase Inhibitors; Adrenergic alpha-Antagonists; Animals; Binding, Competitive; Controlled Clinical Trials as Topic; Endothelins; Enzyme Inhibitors; Humans; Male; Prostate; Prostatic Hyperplasia; Receptors, Adrenergic, alpha; Structure-Activity Relationship

Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.

Topics: Adolescent; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Adult; Aged; Amides; Animals; Binding, Competitive; Humans; Male; Middle Aged; Models, Chemical; Muscle, Smooth; Piperazines; Prazosin; Propylamines; Prostatic Hyperplasia; Rabbits; Rats; Structure-Activity Relationship; Urinary Bladder