title: Salicylamide derivatives related to medroxalol with alpha- and beta-adrenergic antagonist and antihypertension activity.
abstract: Analogues of medroxalol (1) were prepared in which the carboxamide function, the phenolic hydroxy group, and the aralkylamine side chain were modified. N-alkyl-substituted amide analogues of 1 showed diminishing beta-blocking activity with increasing steric bulk of the alkyl group. This allowed the conclusion that deactivation of the phenolic hydroxy group of 1 by the carbonyl group of the amide function is responsible for the beta-adrenergic antagonistic properties of 1. This conclusion was strengthened by the finding that the phenolic O-methyl analogue 5-[2-[[3-(1,3-benzodioxol-5-yl)-1-methylpropyl]amino]-1hydroxyethyl]-2-methoxybenzamide (13) was found to have enhanced beta-adrenergic blocking activity. The finding that 13 also had decreased alpha-blocking activity compared to 1 indicated that the phenolic hydroxy group of 1 enhances alpha-adrenergic antagonism. The finding that 1 and 13 showed such a large difference in relative alpha- to beta-blocking potency while exhibiting approximately equal antihypertensive activity in spontaneously hypertensive rats was surprising. In indicated that pharmacologic properties other than alpha- and beta-adrenergic blockade may contribute to the antihypertensive activity of medroxalol. One of the analogues in which the aralkylamine side chain of 1 was replaced by a fragment of a known alpha-adrenergic receptor blocker, 2-hydroxy-5-[1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]ethyl]benzamide (22), showed an interesting pharmacologic profile of potential therapeutic usefulness.
mesh_terms: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000818:Animals; D000959:Antihypertensive Agents; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004983:Ethanolamines / Q000494:pharmacology*; D066298:In Vitro Techniques; D011817:Rabbits; D051381:Rats; D012457:Salicylamides / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D004983:Ethanolamines; D012457:Salicylamides; C024892:medroxalol