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, -NHSO2CH3). In contrast, substitution at carbon alpha of the phenyl-ethanolamine 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 N of the side chain. Para substitution on the aromatic ring (particularly 4-acylamido substitution) has also yielded cardioselective drugs. Finally, the beta 1-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).
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Institut de Recherches Internationales Servier, Neuilly-sur-Seine, France.
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D000318:Adrenergic beta-Agonists / Q000032:analysis / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000032:analysis / Q000494:pharmacology*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D008024:Ligands; D051381:Rats; D013329:Structure-Activity Relationship
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D008024:Ligands