Purpose: We compared the affinities of a new alpha1-adrenoceptor (AR) antagonist, JTH-601 with those of several alpha1-AR antagonists in human prostates and arteries.
Results: In the functional study, noradrenaline produced concentration-dependent contractions in human prostates and mesenteric arteries. The pA2/pKB values for the antagonists in the human prostate were 9.78 for tamsulosin, 8.84 for JTH-601, 8.39 for WB4101, 8.23 for prazosin, 8.12 for JTH-601-G1 (a main metabolite of JTH-601 in human) and 6.57 for BMY7378. Compared these affinities with those in the mesenteric artery, only JTH-601 and JTH-601-G1 exhibited unique uroselectivity, showing 10- to 20-fold higher affinity for the human prostate than for mesenteric artery. The affinity profile of these antagonists suggested that the noradrenaline-induced contractions in the human prostate and the mesenteric artery were mediated by the alpha1L-AR and alpha1B-AR, respectively. In the competition binding study, the pharmacological profiles of the antagonists against [3H]-prazosin were examined in the human prostate and aorta. The resulting pKi values for JTH-601 and JTH-601-G1 were also approximately 10- to 20-fold higher for the human prostate than for the human aorta.
Conclusion: These results have suggested that JTH-601 and JTH-601-G1 are unique uroselective alpha1-AR antagonists that show higher affinity for the human prostate than for the human arteries.