ly-53857 and sergolexole

Serotonin-induced contraction in porcine coronary artery was studied in ring segments of coronary artery without endothelium. 5-hydroxytryptamine (5-HT), 5-methoxytryptamine (5-MeOT) and alpha-methyl-5-HT (alpha Me-5-HT) concentration-dependently contracted vessels with similar maximal force. The agonist rank order potency was 5-HT > alpha Me-5-HT > 5-MeOT. Neither prazosin (1 microM) nor tetrodotoxin (0.3 microM) significantly altered 5-HT-induced contraction, ruling out activation of alpha-1 adrenoceptors and sodium channels in the contractile response, respectively. Using 5-MeOT as the prototype agonist, cyanopindolol blocked contraction with an antagonist dissociation constant lower than expected for 5-HT1-receptor blockade and ICS 205-930 (10 microM) did not affect 5-MeOT-induced contraction. Five structurally distinct 5-HT2-receptor antagonists (ketanserin, cisapride, spiperone, MDL11939, ICI169369) blocked 5-HT-induced contraction with antagonist dissociation constants similar to reported 5-HT2-receptor affinities. Two ergoline-based 5-HT2-receptor antagonists, LY53857 and sergolexole, blocked 5-HT-induced contraction with antagonist dissociation constants lower than expected for vascular 5-HT2-receptor blockade. Based on the agonist profile and the fact that ICS 205-930 and cyanopindolol were not potent antagonists, the 5-HT receptor-mediating contraction does not represent either the 5-HT1A/B/C/D, 5-HT3 or 5-HT4 receptor. Rather, based on the affinity of several established 5-HT2-receptor antagonists, a 5-HT2 receptor mediates contraction in porcine coronary artery. However, the low antagonist affinity of the ergolines (i.e., LY53857 and sergolexole) suggests that heterogeneity of 5-HT2 receptors may exist among species.

Topics: 5-Methoxytryptamine; Animals; Coronary Vessels; Endothelium, Vascular; Ergolines; In Vitro Techniques; Lysergic Acid; Muscle Contraction; Muscle, Smooth, Vascular; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Swine

Human platelets are known to possess 5HT2 receptors which, when activated, amplify the aggregation response produced by other aggregating agents. Several 5HT2 receptor antagonists, including ketanserin and ritanserin, are known to antagonize serotonin-mediated aggregation of human platelets. In the present study, we document the ability of three ergoline 5HT2 receptor antagonists, LY53857, sergolexole, and LY237733, to antagonize the serotonergic component of the human platelet aggregation response. Potencies of the ergoline esters (LY53857 and sergolexole) and the ergoline amide (LY237733) to inhibit serotonin-amplified platelet aggregation responses were similar to the potencies of ketanserin and ritanserin under the conditions of our study. Furthermore, all five 5HT2 receptor antagonists were capable of fully inhibiting the serotonergic component of the platelet aggregation response. In contrast to these potent ergoline esters and amides, 1-isopropyl dihydrolysergic acid (up to 10(-5)M), a putative metabolite of the ergoline esters, was ineffective under these in vitro conditions. These data are consistent with the high potency of these ergolines as antagonists of 5HT2 receptors and further support the involvement of 5HT2 receptors on human platelets in the amplifying response to serotonin.

Topics: Adult; Ergolines; Female; Humans; Ketanserin; Lysergic Acid; Male; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Receptors, Serotonin; Ritanserin; Serotonin; Serotonin Antagonists

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)

Topics: Administration, Oral; Animals; Corticosterone; Ergolines; In Vitro Techniques; Lysergic Acid; Male; Rats; Rats, Inbred SHR; Receptors, Serotonin; Serotonin Antagonists; Structure-Activity Relationship

The present studies have attempted to evaluate the role of 5-HT2 receptors in the regulation of sexual behavior of male rats by determining the effects of 5-HT2 receptor antagonists, pirenperone, LY53857 and LY281067, and a 5-HT2 receptor agonist, DOI. The administration of 1 mg/kg s.c. pirenperone produced a total suppression of ejaculatory response and lower doses had no effect. However, the administration 0.1 mg/kg s.c. of either LY53857 or LY281067 restored ejaculatory capacity to rats that were unable to ejaculate and produced significant decreases in ejaculatory latency in rats with full sexual capacity. Although all of these agents are 5-HT2 antagonists, LY53857 and LY281067 lack the additional monoaminergic activity of pirenperone. Since the effects of pirenperone were opposite from the effects of the selective 5-HT2 antagonists, the suppressive effects of this agent were probably related to its other monoaminergic activity e.g. alpha 1 antagonist activity. This proposal was supported by the observation that the administration of prazosin, an alpha 1 antagonist, significantly increased ejaculatory latency and suppressed the stimulatory effects of LY53857. In contrast to the stimulatory effects of the selective 5-HT2 antagonists, the administration of DOI, resulted in a suppression of sexual performance, which was blocked by pretreatment with LY53857.

Topics: Amphetamines; Animals; Copulation; Ejaculation; Ergolines; Female; Lysergic Acid; Male; Piperidines; Prazosin; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin Antagonists; Sexual Behavior, Animal