Selective β1-adrenoreceptor blocking activity of newly synthesized acyl amino-substituted aryloxypropanolamine derivatives, DPJ 955 and DPJ 890, in rats

Abstract

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.

Effect of altered AGP plasma binding on heart rate changes by S(−)‐propranolol in rats using mechanism‐based estimations of in vivo receptor affinity (KB,vivo)

“…This is confirmed by the observation that the estimate for affinity in vivo based on total drug (K B ¼ 7.0 nM; 95% confidence interval 3.1-15.4 nM) is different from the in vitro affinity (K B ¼ 1.9 AE 0.48 nM). [31][32][33][34] The findings in the current study are, thus, in agreement with previous studies. Moreover the conclusions are consistent with our previous work on basis of a mechanism-based PKPD model a series of beta-blockers.…”

“…As a consequence, free drug concentrations are considered the best predictor of drug effect for S (−)‐propranolol. This is confirmed by the observation that the estimate for affinity in vivo based on total drug ( K B = 7.0 nM; 95% confidence interval 3.1–15.4 nM) is different from the in vitro affinity ( K B = 1.9 ± 0.48 nM) 31–34. The findings in the current study are, thus, in agreement with previous studies.…”

Mechanism-Based Pharmacodynamic Modeling ofS(–)-Atenolol: Estimation of in Vivo Affinity for the β1-Adrenoceptor with an Agonist-Antagonist Interaction Model

“…Moreover, unique estimates of the K B (affinity) have been obtained that are independent of the administered dose of atenolol. Finally, the obtained estimates of the in vivo K B of atenolol are close to the values obtained in in vitro bioassays (Nandakumar et al, 2005). These findings confirm that in vivo homeostatic feedback mechanisms play a minor role in the estimation of these pharmacodynamic parameters.…”

“…Although ␤ 1 -, ␤ 2 -, and ␤ 3 -adrenoceptor are present in mammalian heart, the positive chronotropic effects of isoprenaline in vivo are caused by ␤ 1 -adrenoceptors (Wellstein et al, 1987;Piercy, 1988;Nandakumar et al, 2005). It is occasionally suggested that ␤ 2 -adrenoceptors are involved in the effect on heart rate.…”

Pharmacokinetic‐pharmacodynamic modelling of S(−)‐atenolol in rats: reduction of isoprenaline‐induced tachycardia as a continuous pharmacodynamic endpoint

“…The tachycardia produced by isoprenaline is primarily due to β ‐adrenoceptor activity in the heart ( Chiu et al ., 2000 ). Although β 1 , β 2 and β 3 adrenoceptora are present in mammalian heart, the positive chronotropic effect of isoprenaline in vivo are brought about by β 1 ‐adrenoceptors ( Wellstein et al ., 1987 ; Piercy, 1988 ; Nandakumar et al ., 2005 ). It is occasionally suggested that β 2 ‐adrenoceptors are also involved in the effect on heart rate, however only a small population of functional β 2 ‐adrenoceptors is present in the heart of WKY rats ( Doggrell and Surman, 1994 ).…”