ABSTRACT
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.
Subject(s)
Adrenergic alpha-Antagonists , Atropine Derivatives/pharmacology , Blood Pressure/drug effects , Acetylcholine/pharmacology , Animals , In Vitro Techniques , Injections, Intravenous , Male , Norepinephrine/antagonists & inhibitors , Rats , Rats, Inbred Strains , Structure-Activity RelationshipABSTRACT
A sensitive and specific radioimmunoassay for haloperidol has been developed. Antibodies were elicited in rabbits immunized with haloperidol hemisuccinate coupled to bovine serum albumin. Optimum sensitivity was obtained with a 1:4000 dilution of the antisera, permitting the detection of as little as 2.6 ng/ml of haloperidol. Major metabolites of haloperidol did not cross-react in the assay. The method does not require an extraction procedure and can be performed using as little as a 5-microliter sample. Haloperidol levels in rat serum and striatum were determined with this method, after the i.v. administration of different dosages of the drug. The distribution and elimination of haloperidol was linear over the dose range to have an elimination half-life of approximately 2.6 hr at all three dosage levels.
