STRUCTURE-ACTIVITY-RELATIONSHIPS IN 1,4-BENZODIOXAN-RELATED COMPOUNDS.4. EFFECT OF ARYL AND ALKYL SUBSTITUENTS AT POSITION 3 ON ALPHA-ADRENOCEPTOR BLOCKING ACTIVITY

The observation that the insertion of a phenyl ring at position 3 of W B 4101 (1) afforded a potent and selective alpha1-adrenoreceptor antag onist, phendioxan (2), prompted us to further investigate that positio n of the 2,3-dihydro-1,4-benzodioxin moiety. Thus the 3-phenyl of 2 wa s replaced by methyl, isopropyl, cyclohexyl, or para-substituted pheny l groups either in a cis or a trans relationships affording compounds 3-17 and 58. The structure of these new derivatives was assigned on th e basis of the coupling constant of hydrogens at positions 2 and 3 and confirmed by a crystallographic study. The blocking activity and rela tive selectivity of 3-17 on alpha1- and alpha2-adrenoreceptors were ev aluated in the isolated rat vas deferens. The results were compared wi th those obtained for 1 and 2. All the compounds, with the exception o f isopropyl and cyclohexyl derivatives 5-8, were effective al-adrenore ceptor antagonists with a significant alpha1/alpha2-selectivity. The l ipophilic and/or electronic character of para substituents of the 3-ph enyl ring does not alter markedly the affinity toward alpha1-adrenorec eptors. However, the 3-p-tolyl derivative 10 was slightly more potent and even more selective than 2.