title: Modulation of vasoactivity and platelet aggregation by selective 5-HT receptor antagonism in humans.
abstract: BACKGROUND
  Distinct serotonin [5-hydroxytryptamine (5-HT)] receptors are involved in platelet aggregation and vasoconstriction. Compounds that simultaneously and selectively inhibit the pertaining 5-HT receptors may therefore represent a therapeutic strategy for arterial thrombosis, observed frequently after atherosclerotic plaque rupture. The vasoactive and antiplatelet effects of the combined 5-HT1B and 5-HT2A receptor blocker SL65.0472-00 were investigated in humans to elucidate the functional involvement of these receptors.
  
  
  METHODS
  Twenty-four volunteers, divided into 2 groups of 12, received an oral dose of 20 mg of SL65.0472-00 or placebo in a randomized, double-blind, crossover study. Pre dose and at 2, 4, and 6 hours after dosing, intra-arterial infusions of 5-HT1B agonist sumatriptan (n = 12) or 5-HT (n = 12) were administered. Forearm blood flow (FBF) was measured using plethysmography, and platelet aggregation was measured using whole blood aggregometry induced by a combination of a threshold collagen concentration and an excess of 5-HT. Treatments were compared using analysis of variance.
  
  
  RESULTS
  After placebo treatment, infusion of 1 ng·kg·min 5-HT induced vasodilatation (FBF +80% change from baseline), whereas infusion of 30 and 80 ng·kg·min 5-HT resulted in vasoconstriction (FBF -25% and -50%). After SL65.0472-00 treatment, all 5-HT doses induced vasodilatation (FBF +25%-60%). Sumatriptan dose dependently decreased FBF (maximally -35%), but this effect was not altered by SL65.0472-00 treatment. 5-HT-induced platelet aggregation was effectively inhibited by 90% after SL65.0472-00 treatment for at least 6 hours.
  
  
  CONCLUSIONS
  SL65.0472-00 has potent antagonistic effect on 5-HT-induced vasoconstriction and platelet aggregation but not on sumatriptan-induced vasoconstriction. This suggests that in humans, SL65.0472-00 is a 5-HT2A blocker without clear 5-HT1B antagonistic activity.
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands. mmoerland@chdr.nl
authors.forename: Matthijs
authors.initials: M
authors.lastname: Moerland
authors.forename: Michiel
authors.initials: M
authors.lastname: Kemme
authors.forename: Anneke
authors.initials: A
authors.lastname: Dijkmans
authors.forename: Luc
authors.initials: L
authors.lastname: Bergougnan
authors.forename: Jacobus
authors.initials: J
authors.lastname: Burggraaf
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010991:Plethysmography; D011804:Quinolines / Q000494:pharmacology*; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D055815:Young Adult
chemical_list: C416534:7-fluoro-2-oxo-4-(2-(4-(thieno(3,2-c)pyridin-4-yl)piperazin-1-yl)ethyl)-1,2-dihydroquinoline-1-acetamide; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011804:Quinolines; D044302:Receptor, Serotonin, 5-HT1B; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D012701:Serotonin; D018170:Sumatriptan