1,4-Benzodioxanes as Reversible and Irreversible Antagonists at Adrenergic Receptors

A series of 1,4-benzodioxanes has been synthesized and examined for activity at adrenergic receptors. The prototype of this series is 2-N,N-diethylaminomethyl-1,4-benzodioxane (I). The corresponding (N-2-chloroethyl derivative was found to be an irreversible α-receptor antagonist, and this irreversible activity was maintained or abolished by the 6- and 7-MeSO₂NH substituents, respectively. I, its 6- and 7-MeSO₂NH derivatives and related nonalkylating compounds showed competitive or potentiating activity toward norepinephrine (NE) in the rat and guinea pig vas deferens. I was the most active competitive antagonist. Additionally, I and some analogs increased the maximum contractile response to NE. Since a similar effect was also exerted by certain compounds on carbachol-induced responses in the guinea-pig vas deferens, it is unlikely that this augmenting effect is exerted at the receptor level and it is speculated that it may be related to increased Ca²⁺ mobilization in the E-C coupling process.