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7. Antihypertensive beta-adrenergic blocking agents: N-aralkyl analogues of 2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine

Author

Thomas F. Lyon, Michael Williams, Charles S. Sweet, K. Mensler, David E. McClure, Andrew W. Raab, W. C. Randall, Edwin A. Risley, John J. Baldwin, George F. Lundell, and Dennis M. Gross

Subjects
Stereochemistry, Pyridines, Adrenergic beta-Antagonists, Alpha (ethology), Binding, Competitive, Dioxanes, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, Receptors, Adrenergic, beta, medicine, Prazosin, Animals, Labetalol, Medroxalol, Beta (finance), Antihypertensive Agents, Cerebral Cortex, Beta-adrenergic blocking agent, Rats, chemistry, Dihydroalprenolol, Molecular Medicine, Enantiomer, medicine.drug
Abstract

An interest in dual-acting antihypertensive agents, specifically those related to (S)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (1), led us to probe the contribution of the side-chain amino substituent in this series. The ability of 1 and its various analogues to displace radiolabeled alpha 1 (WB-4101 and prazosin) and beta (dihydroalprenolol) adrenergic receptor ligands was assessed by receptor-binding techniques. Most of the compounds exhibited high beta-adrenoceptor binding affinities, but only the N-aralkylamino-substituted compounds showed high alpha 1-adrenoceptor affinities. Therefore, the vasodilation shown by 1 was not due to an interaction with the alpha 1 adrenoceptor. The aralkylamino analogues of 1 in spontaneously hypertensive rats and anesthetized dogs exhibited antihypertensive activity and alpha 1-adrenoceptor blocking properties. Unlike the preference shown by beta-adrenoceptors for S enantiomers in this oxymethylene class of beta blockers, the chirality at the secondary hydroxy center made only a minor contribution to the affinity for the alpha 1-adrenoceptor and even less of a contribution to the observed antihypertensive effects. This lack of chiral influence at the hydroxy center confirmed what had been previously observed in more limited studies with the isomers of both labetalol and medroxalol.

Published
1983

9. Antihypertensive beta-adrenergic blocking agents: N-aralkyl analogues of 2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine.

Author

McClure DE, Baldwin JJ, Randall WC, Lyon TF, Mensler K, Lundell GF, Raab AW, Gross D, Risley EA, Sweet CS, and Williams M

Subjects
Animals, Binding, Competitive, Cerebral Cortex metabolism, Dihydroalprenolol metabolism, Dioxanes metabolism, Prazosin metabolism, Rats, Receptors, Adrenergic, beta metabolism, Structure-Activity Relationship, Adrenergic beta-Antagonists pharmacology, Antihypertensive Agents pharmacology, Pyridines pharmacology
Abstract

An interest in dual-acting antihypertensive agents, specifically those related to (S)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (1), led us to probe the contribution of the side-chain amino substituent in this series. The ability of 1 and its various analogues to displace radiolabeled alpha 1 (WB-4101 and prazosin) and beta (dihydroalprenolol) adrenergic receptor ligands was assessed by receptor-binding techniques. Most of the compounds exhibited high beta-adrenoceptor binding affinities, but only the N-aralkylamino-substituted compounds showed high alpha 1-adrenoceptor affinities. Therefore, the vasodilation shown by 1 was not due to an interaction with the alpha 1 adrenoceptor. The aralkylamino analogues of 1 in spontaneously hypertensive rats and anesthetized dogs exhibited antihypertensive activity and alpha 1-adrenoceptor blocking properties. Unlike the preference shown by beta-adrenoceptors for S enantiomers in this oxymethylene class of beta blockers, the chirality at the secondary hydroxy center made only a minor contribution to the affinity for the alpha 1-adrenoceptor and even less of a contribution to the observed antihypertensive effects. This lack of chiral influence at the hydroxy center confirmed what had been previously observed in more limited studies with the isomers of both labetalol and medroxalol.

Published
1983
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