title: 5-Hydroxytryptamine2 receptor antagonist activity of the acid metabolite (1-isopropyl dihydrolysergic acid) of the ergoline ester, sergolexole (LY281067).
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)
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: M L
authors.initials: ML
authors.lastname: Cohen
authors.forename: C J
authors.initials: CJ
authors.lastname: Parli
authors.forename: R W
authors.initials: RW
authors.lastname: Fuller
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003345:Corticosterone / Q000097:blood; D004873:Ergolines / Q000378:metabolism* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008237:Lysergic Acid / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004873:Ergolines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C062146:1-isopropyldihydrolysergic acid; D008237:Lysergic Acid; C054583:sergolexole; C032663:LY 53857; D003345:Corticosterone