Characterization of benextramine as an irreversible alpha-adrenergic blocker and as a blocker of potassium-activated calcium channels.
An irreversible alpha-adrenergic blocker, benextramine [N,N'-bis(o-methoxybenzylamine-n-hexyl)-cysteamine] was used as a probe to study the possible interrelationship between alpha-adrenoceptors and the K+-activated Ca2+-channels. Benextramine, a tetraamine disulfide, acts irreversibly both on the alpha 1-adrenoceptor (t 1/2 = 3 min) and the alpha 2-adrenoceptors. These studies were carried out on rat brain synaptosomes, [3H]prazosin and [3H]clonidine binding. Benextramine blocked Ca2+ influx in rat brain synaptosomes under both depolarizing (75 mM KCl) and normal conditions (5 mM KCl). Its action at the channel is reversible with IC50 = 10 +/- 5 microM of the net Ca2+ influx. This makes benextramine a most potent Ca2+ blocker compared to verapamil or nicardipine (IC50 = 200 microM and 170 microM, respectively). Pretreatment of rat brain slices with benextramine gave a synaptosomal preparation which was devoid of either alpha 1-adrenergic or alpha 2-adrenergic binding capacity due to the irreversible binding of benextramine, but with an undisturbed Ca2+ influx. Thus, these results suggest that the alpha-adrenoceptors and the Ca2+-channels are independent of each other, and that full occupancy of the alpha-receptors does not affect the net calcium flux.
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002121:Calcium Channel Blockers; D003538:Cystamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D011188:Potassium / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D002121:Calcium Channel Blockers; C029998:benextramine; D003538:Cystamine; D011188:Potassium