Pharmacological characterization of [3H]-JTH-601, a novel α1-adrenoceptor antagonist: Binding to recombinant human α1-adrenoceptors and human prostates

Abstract Several α 1 -adrenoceptor (AR) selective antagonists are now widely used to improve lower urinary tract symptoms in benign prostatic hyperplasia patients. However, these drugs often result in orthostatic hypotension, because of their poor uroselectivity; the blockade of α 1 -AR not only in prostate but also in vasculature. Here we have investigated uroselectivity of JTH-601, a newly developed antagonist, in radioligand binding experiment using recombinant human α 1 -AR subtypes and human prostate. In saturation experiments, [ 3 H]-JTH-601 showed subtype selectivity: high affinity to α 1a -AR (pKd; 9.88±0.09), lower affinity to α 1b -AR (pKd; 8.96±0.17) and no specific binding at concentrations up to 3000 pM to α 1d -AR. In competition experiments, JTH-601 and its metabolic compound (JTH-601-G1) also showed α 1a -AR selectivity, exhibiting approximately 5 times higher affinity for α 1a -AR than for α 1b -AR, 10 to 20 times higher affinity than for α 1d -AR, respectively. [ 3 H]-JTH-601 also bound to human prostate membranes in monophasic manner with high affinity constant (pKd; 9.89±0.12, Bmax=123.6±16 fmol/mg protein). JTH-601 is a unique α 1 -AR antagonist that shows high affinity and selectivity for human recombinant α 1a - and human prostate. This new compound is useful for understanding α 1 -AR pharmacology and may have a therapeutic value.