Interaction between dilazep and alpha-adrenoceptors

Dilazep, 1,4-bis-[3-(3,4,5-trimethoxybenzoyl-oxy)propyl]perhydro-1,4-diazep ine, is a novel antianginal agent with an unusual chemical structure. The drug is a weak calcium antagonist. In pithed rats dilazep (10-100 mg/kg i.v.) caused a transient hypotensive effect which was accompanied by a strong and persistent reduction in heart rate. Similarly as observed for other, more potent calcium antagonists dilazep (10-100 mg/kg) counteracted the vasoconstriction, evoked by the stimulation of postsynaptic alpha 2-adrenoceptors with the selective agonist B-HT 920. The antagonism proved noncompetitive. The vasoconstriction, induced upon selective stimulation of postsynaptic alpha 1-adrenoceptors with methoxamine, however, was hardly influenced by dilazep. These findings are in accordance with the calcium-antagonistic activity of dilazep, demonstrable at relatively high doses. From radioligand-binding studies it was concluded that dilazep is an extremely weak antagonist of alpha 1-adrenoceptors, whereas it does not possess any measurable affinity towards alpha 2-adrenoceptors. It seems unlikely that the antianginal activity of dilazep can be fully explained by its weak calcium-antagonistic potency. However, the bradycardic effect of dilazep is probably relevant to its antianginal activity.