STUDIES WITH ABANOQUIL (UK-52,046) A NOVEL QUINOLINE ALPHA-1-ADRENOCEPTOR ANTAGONIST .2. DURATION OF ACTION, PHARMACOKINETICS AND CONCENTRATION-EFFECT RELATIONSHIPS IN NORMOTENSIVE SUBJECTS

1 This study further examines the quinoline-derivative abanoquil with particular respect to the duration of its alpha-1-adrenoceptor antagonist activity and its concentration-effect relationship following a single intravenous bolus dose of 0.5-mu-g kg-1 in young, normotensive males. 2 Alpha-1-adrenoceptor antagonism (as assessed by phenylephrine pressor responses) was detectable for up to 12 h post dosing: at 12 h there was a significant 1.5-fold rightward shift (95% CI: 2.2 to 1.1) of the pressor dose-response curve for diastolic blood pressure. 3 Despite evidence of substantial alpha-1-adrenoceptor antagonism abanoquil had no significant effect on blood pressure, supine and erect, but there were small and statistically significant increments in heart rate. 4 The degree of alpha-1-adrenoceptor antagonism was related to whole blood concentrations abanoquil: the PD-ratios of phenylephrine pressor responses performed at 1, 6, and 12 h post dosing were significantly correlated with log drug concentrations (r = 0.57 for systolic (P < 0.05) and r = 0.78 for diastolic blood pressure (P < 0.005). 5 In conclusion, abanoquil produced significant alpha-1-adrenoceptor antagonism which was related to circulating drug concentrations. The absence of other significant cardiovascular effects suggests that abanoquil warrants further clinical study as an antiarrhythmic agent.