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5-Hydroxytryptamine2 Receptor Antagonist Activity of the Acid Metabolite (1-isopropyl Dihydrolysergic Acid) of the Ergoline Ester, Sergolexole (LY281067)

5-Hydroxytryptamine2 Receptor Antagonist Activity of the Acid Metabolite (1-isopropyl Dihydrolysergic Acid) of the Ergoline Ester, Sergolexole (LY281067)

M L Cohen, C J Parli, R W Fuller

J Pharmacol Exp Ther. 1989 Dec;251(3):1006-11.

PMID: 2600800

Abstract:

The ergoline esters, LY53857 [6-methyl-1-(1-methylethyl)ergoline-8-carboxylic acid 2-hydroxy-1-methylpropylester (Z)-2-butenedioate] and sergolexole (LY281067) ([trans-(8 beta)]6-methyl-1-[1-methylethyl]ergoline-8-carboxylic acid, 4-methoxycyclohexyl ester (maleate salt] are potent 5-hydroxytryptamine2 (5-HT2) receptor antagonists in vivo and in vitro. Ester hydrolysis of either compound results in the formation of 1-isopropyl dihydrolysergic acid which in rats is a major metabolite of these ergoline esters. The present study details the pharmacological activity of 1-isopropyl dihydrolysergic acid and examines its relative contribution to the 5-HT2 receptor antagonism seen after sergolexole in rats. In vitro, 1-isopropyl dihydrolysergic acid was a competitive antagonist of 5-HT2 receptors in the rat jugular vein, with a dissociation constant approximating 10(-7) M. After i.v. administration to pithed rats, 1-isopropyl dihydrolysergic acid also antagonized the pressor response produced by serotonin, an in vivo estimate of vascular 5-HT2 receptor blockade. In fact, after i.v. administration, 1-isopropyl dihydrolysergic acid was nearly one-third as potent as sergolexole. After i.p. administration, 1-isopropyl dihydrolysergic acid was approximately one-tenth to one-thirtieth as potent as sergolexole. Likewise, 1-isopropyl dihydrolysergic acid antagonized central 5-HT receptors as measured by blockade of quipazine-induced increases in serum corticosterone concentration in rats and was approximately one-twentieth as potent as sergolexole.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP5786685	Quipazine maleate salt		5786-68-5	Price

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