Alpha2-adrenoceptor antagonism and other pharmacological antagonist properties of some substituted benzoquinolizines and yohimbine in vitro

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Abstract
Comparison of pA2 values for antagonism of clonidine induced inhibition of the electrically evoked contraction of the rat isolated vas deferens (α 1-adrenoceptors) and antagonism of contractions to methoxamine on the rat isolated anococcygeus (α 2-adrenoceptors) showed a group of substituted benzoquinolizines (Wy 25309, 26392 and 26703) to be more potent and more selective α 2-adrenoceptor antagonists than yohimbine. The benzoquinolizines and yohimbine enhanced stimulation-evoked overflow of tritium from rabbit isolated pulmonary arteries preloaded with [3H]-noradrenaline, as expected for α 2-adrenoceptor antagonists. In contrast to the results on the rat vas deferens, yohimbine was more potent than the benzoquinolizines. At higher concentrations all the α-adrenoceptor antagonists reduced the stimulation-evoked contraction of the pulmonary artery. The benzoquinolizines were competitive antagonists of 5-hydroxytryptamine on the rat isolated ileum. Wy 25309 showed only weak activity (pA2=5.21) whereas Wy 26703 was more potent (pA2=7.25). Yohimbine was a potent antagonist of 5-hydroxytryptamine. Wy 26703 was the only compound to have histamine antagonist effects in the guinea pig isolated ileum and to antagonise the chronotropic effect of isoprenaline on the isolated atria of the guinea pig and in both instances activity was weak (pA2 values 5.3 and 5.5 respectively). Yohimbine reduced the spontaneous beating of the atria at 3×10−6 M. No compound at 10−5 M antagonised acetylcholine on the guinea pig ileum. These novel substituted benzoquinolizines should be useful experimental compounds for the study of α-adrenoceptors mediated responses.

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