Structure-activity requirements for hypotension and alpha-adrenergic receptor blockade by analogues of atropine.
The hypotensive action of various antimuscarinic compounds structurally related to atropine was studied in conscious, unanesthetized rats. The alpha-adrenolytic activity of these agents was assessed both in vivo (blockade of norepinephrine-induced pressor response) and in vitro (displacement of [3H]WB-4101 binding). Benztropine, homatropine and hyoscyamine caused hypotension and produced alpha-adrenergic receptor blockade similar to atropine. Other analogues were either inactive (atroscine, scopolamine, tropic acid and tropine) or evoked nonspecific changes in blood pressure and lacked alpha-adrenolytic activity (benactyzine, eucatropine, methylatropine, methylhomatropine and methylscopolamine). Based on these data, we propose the following structure-activity relationship for hypotension and alpha-adrenolytic activity: (a) the tropine moiety is inactive unless it is attached to another group by an ester linkage, (b) chemical modification of the tropine moiety, including quaternization, decreases potency, (c) the d-stereoisomer appears to be more potent than the corresponding 1-form.
D000109:Acetylcholine / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists; D000818:Animals; D001286:Atropine Derivatives / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000317:Adrenergic alpha-Antagonists; D001286:Atropine Derivatives; D000109:Acetylcholine; D009638:Norepinephrine