Structure-Activity Relationships as a Response to the Pharmacological Differences in Beta- Receptor Ligands

With a few notable exceptions, beta-receptor ligands (agonists and antagonists) belong to the aryl- or heteroaryl-ethanolamine series and to the aryl- or heteroaryl-oxypropanolamine series Structure-activity relationships for beta-adrenergic agonists show that a secondary amine in the phenylethanolamine side chain ending is essential for receptor stimulation. The 3,4-dihydroxyphenyl groups may be replaced by "phenol equivalents" (-CH2OH, -NHCONH2 , -CHOH, - NHS02CH3 ) . In contrast, substitution at carbon alpha of the phenylethanolamine side chain decreases or suppresses beta-adrenergic activity The general requirements for beta-adrenergic blocking activity in the aryl- or heteroaryl-oxypropanolamine are as follows: (1) the potency of beta-blockade is conferred by a branched alkyl group (isopropyl or tert-butyl) grafted on the terminal amino N, and by the nature and position of a substituent on the aromatic ring: ortho-substituted compounds (especially when they have an hetero-atom in alpha) are the most potent ones. (2) The cardioselectivity is improved by the attachment of 3,4-dimethoxyphenylethyl,4-amide-substituted phenoxyethyl or acylamino-alkyl moieties to the terminal amino Ν of the side chain. Para substitution on the aromatic ring (particularly 4-acylamido substitution) has also yielded cardioselective drugs. Finally, the beta^selectivity is strongly and negatively correlated with lipophilicity. (3) Intrinsic sympathomimetic activity can be modulated by aromatic nucleus variations, particularly by hydroxyl- equivalents (electron withdrawing groups) on meta- and para-positions (3,4-substitutions). Am J Hypertens 1989; 2:245S–251S