title: LY215840, a high-affinity 5-HT7 receptor ligand, blocks serotonin-induced relaxation in canine coronary artery.
abstract: The canine coronary artery possesses a smooth muscle relaxant serotonin (5-HT) receptor distinct from previously characterized 5-HT receptors. On the basis of the ability of LY53857 to block weakly coronary smooth muscle relaxation to 5-HT, we examined several structurally related ergolines in endothelium denuded rings of canine coronary artery precontracted with PGF2 alpha (10 microM). 5-HT (10 nM-100 microM)-induced relaxation was antagonized competitively by the ergoline esters LY53857 (-log KB = 6.5) and sergolexole (-log KB = 6.4) and by the ergoline amide amersergide, (-log KB = 6.7). In contrast to the relatively low affinity of these ergolines, LY215840, another ergoline amide, antagonized 5-HT-induced relaxation in a competitive manner with the highest affinity (-log KB = 8.3). This effect was independent of the 5-HT2 receptor affinity of these ergolines, because LY215840, LY53857, sergolexole and amesergide all possessed similar 5-HT2 receptor affinity. Further, all four ergolines possessed affinity for the human 5-HT7 receptor, and LY215840 had the highest 5-HT7 receptor affinity (Ki = 14.7 nM). Finally, in vascular smooth muscle under basal tone, LY215840 (1 microM) blocked the relaxant response to high concentrations of 5-HT and 5-MeOT without altering their contractile potency. LY215840 (1 microM) did not alter contraction to sumatriptan, an agent that lacks relaxant activity. In contrast, LY215840 (1 microM) markedly potentiated contraction to 5-carboxamidotryptamine, the most potent coronary relaxant agonist and the agonist with the highest 5-HT7 receptor affinity. The ability of LY215840 to block the relaxant 5-HT receptor in canine coronary artery may reflect its 5-HT7 receptor antagonist activity and make it a useful tool to probe the relationship between the 5-HT7 receptor and the coronary vasoactive properties of 5-HT.
authors.affiliation: Lilly Research Laboratories, Paramus, New Jersey, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Cushing
authors.forename: J M
authors.initials: JM
authors.lastname: Zgombick
authors.forename: D L
authors.initials: DL
authors.lastname: Nelson
authors.forename: M L
authors.initials: ML
authors.lastname: Cohen
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008237:Lysergic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011869:Radioligand Assay; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D012702:Serotonin Antagonists; C074025:LY 215840; D012701:Serotonin; D008237:Lysergic Acid