2-(beta-(3-iodo-4-hydroxyphenyl)ethylaminomethyl)tetralone and naftopidil

The pharmacological profiles of the alpha1-adrenoceptor antagonists naftopidil, tamsulosin and prazosin were studied in an anesthetized dog model that allowed the simultaneous assessment of their antagonist potency against phenylephrine-mediated increases in prostatic pressure and mean blood pressure. The intravenous administration of each of these compounds dose-dependently inhibited phenylephrine-induced increases in prostatic pressure and mean blood pressure. To further assess the ability of the three compounds to inhibit phenylephrine-induced responses, the doses required to produce a 50% inhibition of the phenylephrine-induced increases in prostatic and mean blood pressure and the selectivity index obtained from the ratio of those two doses were determined for each test compound. Forty minutes after the intravenous administration of naftopidil, the selectivity index was 3.76, and those of tamsulosin and prazosin were 1.23 and 0.61, respectively. These findings demonstrated that naftopidil selectively inhibited the phenylephrine-induced increase in prostatic pressure compared with mean blood pressure in the anesthetized dog model. The selectivity of naftopidil for prostatic pressure was the most potent among the test compounds. In addition, using cloned human alpha1-adrenoceptor subtypes, naftopidil was selective for the alpha1d-adrenoceptor with approximately 3- and 17-fold higher affinity than for the alpha1a- and alpha1b-adrenoceptor subtypes, respectively. The selectivity of naftopidil for prostatic pressure may be attributable to its high binding affinity for alpha1a- and alpha1d-adrenoceptor subtypes.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Anesthesia; Animals; Binding, Competitive; Blood Pressure; CHO Cells; Cricetinae; Dogs; Humans; Male; Naphthalenes; Phenethylamines; Phenylephrine; Piperazines; Pressure; Prostate; Radioligand Assay; Receptors, Adrenergic, alpha-1; Recombinant Proteins; Tetralones

Newly developed alpha1-adrenoceptor antagonists including naftopidil are free from the "prazosin-like" side effect of orthostatic hypotension and associated symptoms. We investigated the mechanism for the differential effects of naftopidil and prazosin on the development of postural hypotension, with special attention on their selectivity for the alpha1-adrenoceptor subtype. We observed that head-up tilt caused a similar extent of drop in mean arterial pressure in control, naftopidil (1 mg/kg)- or prazosin (10 microg/kg)-treated rats; however, the tilt-induced postural hypotension was recovered within 2 min in the naftopidil-treated group, but not in the prazosin-treated group. Comparing an inhibitory effect on noradrenaline-induced contraction in the rat aorta and portal vein, we found that naftopidil was sixfold less potent in the portal vein, while prazosin showed similar potency in both tissues. Reverse transcription-polymerase chain reaction analysis showed that the expression of alpha1d-adrenoceptor mRNA predominated in the aorta, while that of alpha1b-adrenoceptor mRNA predominated in the portal vein. Using cloned rat alpha1-adrenoceptor subtypes, we found that naftopidil was selective for the alpha1d-subtype with approximately ninefold higher affinity than at the other subtypes. These results show that the pharmacological character of naftopidil, combined with the differential expression of the alpha1-adrenoceptor subtype in the artery and the vein, may partly explain the differential effect of naftopidil and prazosin on head-up tilt-induced hemodynamic responses.

Topics: Adrenergic alpha-Antagonists; Animals; Base Sequence; CHO Cells; Cricetinae; DNA Primers; Hypotension, Orthostatic; Iodine Radioisotopes; Male; Naphthalenes; Phenethylamines; Piperazines; Prazosin; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Recombinant Proteins; RNA, Messenger; Tetralones