Selectivity of Benzodioxane α-Adrenoceptor Antagonists for α₁-and α₂-Adrenoceptors Determined by Binding Affinity

Abstract

A series of benzodioxane derivatives, structurally related to WB 4101 and piperoxan as well as prazosin and its two analogues UK-18,596 and UK-33,274, was studied with respect to their affinity for alpha 1-and alpha 2-adrenoceptors identified by 3H-prazosin (specific activity 33 Ci/mmol) and 3H-clonidine (specific activity 26.7 Ci/mmol), respectively, in isolated rat brain membranes. The structural variations made in these molecules gave rise to pronounced differences in affinity for alpha 1-adrenoceptors, whereas their binding affinity for alpha 2-adrenoceptors only slightly varied. Apart from piperoxan and its analogues, which showed some preference for alpha 2-adrenergic binding sites, all benzodioxane-like structures displayed a general selectivity for the alpha 1-adrenoreceptor sites labeled with 3H-prazosin. The drugs were 5-50 times more potent in inhibiting 3H-prazosin than 3H-clonidine from their specific binding sites in rat brain membranes. The highest alpha 1 selectivity was found for prazosin and UK-33,274. Within the present series of WB 4101-related benzodioxane compounds, the affinity for alpha 1-adrenoceptors is greatly reduced by alkyl substitution at the secondary amino nitrogen in the side chain. Ortho substitution of the phenyl moiety with methoxy increased affinity as did hydroxy at the para position. The side chain oxygen atom can be deleted or substituted by methylene without great loss in 3H-prazosin displacing effectiveness. The affinity for alpha 1-adrenoceptors was profoundly influenced by the configuration of the molecule. Upon introducing a second chiral center through a methyl group, the two resulting racemates differ 10-fold in activity and selectivity towards alpha 1-adrenoceptors. One of these racemates was even slightly more selective than WB 4101 itself. The selectivity of the drugs to bind to alpha 1-and alpha 2-adrenoceptors corresponded well with their in vivo selectivity to antagonize alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats. It is suggested that a systematic study of the structure-affinity relationship in benzodioxane antagonists may provide potent and selective blocking drugs of alpha 1-adrenoceptors.

Pharmacological activity of ACC‐7513, a selective α‐adrenoceptor and 5‐hydroxytryptamine receptor blocking agent

“…Some benzodioxanes such as doxazosin (Timmermans et al, 1980a) and the close structural analogue of ACC-7513, WB 4101 (Butler & Jenkinson, 1978;Mottram, 1980;Drew, 1982;Ruffolo et al, 1983) are selective for postsynaptic o-adrenoceptors, while others, e.g., piperoxan (Timmermans et al, 1980b) and RX 781094 (Dabire et al, 1981;Doxey et al, 1983) are selective for presynaptic receptors, and still others, may be relatively non-selective. In a recent binding study Timmermans et al (1983) concluded that benzodioxanes other than piperoxan and its analogues are selective for a,-adrenoceptors. If ACC-7513 should be fairly potent at presynaptic a-adrenoceptors this might account for the relatively small reductions in blood pressure observed, since reductions in blood pressure due to postsynaptic a-adrenoceptor blockade would be partially offset by the effective enhancement of sympathetic tone due to presynaptic x-adrenoceptor blockade.…”