Effect of KMD-3213, an alpha(1A)-adrenoceptor antagonist, on the prostaticurethral pressure and blood pressure in male decerebrate dogs

Background: KMD-3213 is an alpha (1A)-adrenoceptor-selective antagonist cur rently being developed for the treatment of urinary outlet obstruction in p atients with benign prostatic hyperplasia. In the present study, the urosel ectivity of KMD-3213 was evaluated and compared with that of prazosin and t amsulosin in a decerebrate dog model. Methods: Intercollicular decerebration was carried out in male mongrel dogs under anesthesia. The inhibitory effects of intravenously and intraduodena lly administered compounds on the increase in intraurethral pressure (IUP) induced by electrical stimulation of the hypogastric nerve were estimated. Systemic blood pressure was measured simultaneously. Results: The alpha (1)-antagonists tested produced a dose-dependent inhibit ion of the induced IUP response and decreased mean blood pressure (MBP). Th e ID50 of KMD-3213, tamsulosin and prazosin for IUP (dose required to inhib it the increase in IUP by 50%) was 3.15, 1.73 and 11.8 mug/kg i.v., respect ively, and the ED20 for the hypotensive effect (dose required to reduce MBP by 20%) was 8.03, 0.59 and 2.46 mug/kg i.v., respectively. The data indica te that uroselectivity (ED20/ID50) of KMD-3213 is 12- and 7.5-fold higher t han that of prazosin and tamsulosin, respectively. When the drugs were admi nistered intraduodenally, KMD-3213 was sufficiently absorbed from the diges tive tract and continued to demonstrate at least 3.8-fold higher uroselecti vity than tamsulosin. Conclusion: Based on these findings, KMD-3213 appears to be an effective or ally active compound for decreasing urethral resistance during micturition that does not induce any negative cardiovascular effects in patients with b enign prostatic hyperplasia.