VINYLOGS AND ACETYLENYLOGS OF BETA-ADRENERGIC AGENTS

Vinylogous (Groups III and V) and acetylenologous (Group IV) analogs o f the classical beta-adrenergic agents - stimulants and blockers - wer e prepared in order to evaluate the effect of degree of saturation, po sition of unsaturation and rigidity of the chain linking the aromatic ring and the amino containing functional group on biological activity. Derivatives from Group III, which represent 4-aryl-3-butenyl-2-ol-ami ne analogs of Group II, retained beta(1)-adrenoceptor antagonist activ ity albeit substantially less potent (50-200-fold) than that possessed by their aryloxy counterparts. Consistent with the SAR for Group II c ompounds, substitution at position 2 of the aromatic ring yielded the most potent antagonists (5a, 5d, 5g), with K-B's ranging from 73-93 nM while 3,4-dichloro substitution (5e) markedly reduced antagonist pote ncy (K-B = 2,400 nM). Agonist activity was also noted for 5b and 5d, s uggesting that these compounds may be best classified as partial agoni sts. Representatives from Groups IV and V were inactive as antagonists at the beta(1)-adrenoceptor confirming the importance of the spatial relationship between the hydroxyl and the amino nitrogen.