Selective beta(1)-adrenoreceptor blocking activity of newly synthesized acyl amino-substituted aryloxypropanolamine derivatives, DPJ 955 and DPJ 890, in rats.

The in-vivo beta-adrenoreceptor antagonistic activity of test compounds DPJ 955 and DPJ 890 was assessed against beta-adrenoreceptor agonist (isoprenaline) induced tachycardia in anaesthetized rats. The selectivity to block isoprenaline responses on different &beta-adrenoreceptor subtypes (beta(1), beta(2) and beta(3)) of the test compounds was carried out on isolated rat right atria, isolated rat uterus and isolated rat colon preparations, respectively. Intravenous injection of isoprenaline alone in anaesthetized rats caused hypotension and tachycardia. DPJ 955 or DPJ 890 alone produced a fall in mean arterial pressure and bradycardia in a dose-dependent manner. Administration of isoprenaline to anaesthetized rats pre-treated with test compounds significantly blocked both the tachycardial and hypotensive responses induced by isoprenaline. The test compounds shifted the concentration response curves of isoprenaline towards the right for isolated rat right atrial preparations, rat uterus and rat colon, indicating beta(1), beta(2) and beta(3) adrenoreceptor blockade, respectively. The selectivity ratio for beta(1)/beta-adrenoreceptors to DPJ 955 and DPJ 890 was 64.6 and 83.2, respectively. DPJ 890 was more potent in blocking beta(1)-adrenoreceptors and was more selective towards beta(1) receptors than to other beta-adrenoreceptor subtypes. In conclusion, DPJ 955 and DPJ890 have beta-adrenoreceptor blocking activity with high selectivity for the beta(1)-adrenoreceptor subtype.

Study of beta-adrenoreceptor antagonistic activity of DPJ 904 in rats.

beta-Adrenoreceptor antagonistic activity of a newly synthesized compound was evaluated in vivo by measuring the mean arterial blood pressure and heart rate of urethane-anesthetized rats treated with isoprenaline. In vitro beta(1)-, beta(2)- and beta(3)-antagonism was studied using isolated rat right atria, isolated rat uterus and isolated rat colon preparations, respectively, in comparison to isoprenaline response. DPJ 904 (1, 3 and 10 mg/kg, i.v.) produced dose-dependent hypotensive and bradycardia response in anesthetized rat. DPJ 904 (1, 3 and 10 mg/kg, i.v.) significantly inhibited both the tachycardial effects and hypotensive response induced by isoprenaline. DPJ 904-antagonized isoprenaline induced positive chronotropic effects of isolated rat right atria and a uterine relaxant effect indicating beta(1)- and beta(2)-blockade. The parallel shift to the right of the concentration-response curve of isoprenaline in the presence of DPJ 904 in KCl (30 mmol/l) induced contraction of the rat colon suggesting that DPJ 904 also possessed beta(3)-adrenoreceptor antagonistic activity. The selectivity to beta(1)-adrenoreceptor was nearly 20.5 times greater than to beta(2)-adrenoreceptor. The present study indicates that DPJ 904 possesses beta-adrenoreceptor antagonistic activity with slightly more affinity to the beta(1)-adrenoreceptor subtype.