Antihypertensive beta-adrenergic blocking agents: N-aralkyl analogues of 2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine.
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.
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D004082:Dihydroalprenolol / Q000378:metabolism; D004146:Dioxanes / Q000378:metabolism; D011224:Prazosin / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013329:Structure-Activity Relationship
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D004146:Dioxanes; D011725:Pyridines; D011943:Receptors, Adrenergic, beta; D004082:Dihydroalprenolol; C021276:MK 761; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D011224:Prazosin