Z-350, a new chimera compound possessing α1-adrenoceptor antagonistic and steroid 5α-reductase inhibitory actions

Abstract

The effects of Z-350, (S)-4-[3-(4-{1-(4-methyl-phenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]propoxy} benzoyl)indole-1-yl]butyric acid hydrochloride, a newly synthesized compound possessing alpha-adrenoceptor antagonistic and steroid 5alpha-reductase inhibitory actions, were studied in vitro. In functional experiments, Z-350 shifted the concentration/response curve for the phenylephrine-induced contraction of rabbit prostate, urethra and aorta to the right with pA2 values of 8.04, 7.57 and 7.13, respectively. The binding affinity of Z-350 for alpha1-adrenoceptors in rabbit prostate, urethra and aorta were estimated by the displacement of [3H]prazosin. The pKi values for this action of Z-350 were 7.53, 7.95 and 7.62 for the prostate, urethra and aorta, respectively. alpha1-Adrenoceptor subtype selectivities were studied in the submaxillary gland (r(1A) and liver (alpha1B) of rat. Z-350 inhibited the specific binding of [3H]prazosin to alpha1A and (alpha1B-adrenoceptors with pKi values of 7.82 and 7.29, respectively. Z-350 inhibited rat prostatic steroid 5alpha-reductase non-competitively with a pIC50 of 8.42. These results indicate that Z-350 is a alpha1-adrenoceptor antagonist and is a steroid 5alpha-reductase inhibitor. It is expected that Z-350 will be a candidate drug for the treatment of benign prostatic hyperplasia.

Hormonal Effects of Z-350, Possessing Steroid 5 a-Reductase Inhibitory and a ι-Adrenoceptor Antagonistic Actions, in the Rat

“…The dose of Z-350 required for a significant reduction of prostatic weight in normal rats was 30 mg/kg. This was higher than that previously reported for the inhibition of testosteroneinduced prostatic growth in castrated rats (17). Similar observations have been reported previously.…”

“…Furthermore, Z-350 showed no effects on either the weight of the prostate and seminal vesicles in castrated rats or the weight of the uterus in normal or 17b-estradiol-treated female rats, indicating that Z-350 has no androgenic, estrogenic or anti-estrogenic activity. These findings, together with our recent report that Z-350 does not reduce prostatic growth induced by dihydrotestosterone in castrated rats (17), indicate that Z-350 reduces prostatic weight only by inhibition of 5a-R, without affecting serum hormonal levels. This result is in agreement with those for other 5a-R inhibitors (19,31).…”

“…It has previously been reported that the reduction in prostatic dihydrotestosterone levels caused by finasteride, a competitive inhibitor of 5a-R (25), is accompanied by an apparent increase in prostatic testosterone levels (26), and it has been suggested that the inhibitory effect of finasteride may gradually diminish because of these increased testosterone levels (22). The increased testosterone level would not be expected to interfere with the inhibitory action of Z-350, since Z-350 inhibits prostatic 5a-R non-competitively (16). Thus, the inhibitory potency of Z-350 would probably not be influenced by increased prostatic testosterone levels.…”

“…On the basis of the concept that combined activity (i.e., a 1-adrenoceptor blocking and 5a-R inhibition) may be more beneficial for the treatment of BPH than each activity alone, we recently reported the pharmacological profile of Z-350, which possesses a1-adrenoceptor blocking and 5a-R inhibitory activity, in vitro (16) and in vivo (17). Z-350 inhibited rat prostatic 5a-R in a non-competitive manner and prevented testosterone-induced re-growth of the prostate in castrated rats.…”

Anti‐Androgen Effects of Extracts and Compounds from Ganoderma lucidum

“…The assay for growth suppression of the rat prostate was performed as described by Fukuta et al [32]. The testes of SD rats were removed at four weeks of age under light anesthesia with pentobarbital.…”