title: The in vivo pharmacological profile of eletriptan (UK-116,044): a potent and novel 5-HT(1B/1D) receptor agonist.
abstract: The anti-migraine drug, eletriptan [(R)-3-(1-methyl-2-pyrrolidinylmethyl)-5-[2-(phenylsulphonyl )ethyl]-1 H-indole; UK-116,044], is a novel 5-HT(1B/1D) receptor agonist. In this paper, the regional vasoconstrictor profile of eletriptan, in comparison with sumatriptan, was examined in the anaesthetised dog. The inhibitory actions of eletriptan on neurogenic inflammation in rat dura mater were also assessed. In the anaesthetised dog, eletriptan (1-1000 microg kg(-1) i.v.) produced a dose-dependent reduction of carotid arterial blood flow with a similar potency and maximum effect to sumatriptan (ED(50) values: eletriptan and sumatriptan, 12 and 9 microg kg(-1), i.v., respectively). However, eletriptan exhibited a significantly lower potency than sumatriptan in reducing coronary artery diameter (ED(50) values: 63 and 19 microg kg(-1), i.v., respectively, P<0.05). In the femoral circulation, sumatriptan caused a significant reduction in arterial blood flow (ED(50) 35 microg kg(-1) i.v.) whereas eletriptan (1-1000 microg kg(-1) i.v.) had no significant effect upon femoral arterial blood flow when compared to vehicle-treated animals. In rats, eletriptan (30-300 microg kg(-1) i.v.) administered prior to electrical stimulation of the trigeminal ganglion produced a dose-related and complete inhibition of plasma protein extravasation in the dura mater (mean extravasation ratio: control 1.9; eletriptan 1.0, minimum effective dose 100 microg kg(-1), P<0.05). The potency and maximum effect of eletriptan was identical to that of sumatriptan in this model. When administered during a period of continual stimulation of the trigeminal nerve, eletriptan (100 microg kg(-1) i.v.) produced a complete inhibition of plasma protein extravasation. The ability to reduce canine carotid arterial blood flow and inhibit neurogenic inflammation in rat dura mater suggests that vascular and neurogenic mechanisms may contribute to eletriptan's clinical efficacy in migraine patients. In addition, eletriptan exhibits some selectivity for reducing carotid arterial blood flow when compared with femoral arterial blood flow and coronary artery diameter, in the anaesthetised dog.
authors.affiliation: Department of Discovery Biology, Pfizer Central Research, Sandwich, CT13 9NJ, Kent, UK.
authors.forename: P
authors.initials: P
authors.lastname: Gupta
authors.forename: P
authors.initials: P
authors.lastname: Butler
authors.forename: N B
authors.initials: NB
authors.lastname: Shepperson
authors.forename: A
authors.initials: A
authors.lastname: McHarg
mesh_terms: D000758:Anesthesia; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001798:Blood Proteins / Q000493:pharmacokinetics; D002199:Capillary Permeability / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004388:Dura Mater / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism; D014363:Tryptamines
chemical_list: D001798:Blood Proteins; D007211:Indoles; D011759:Pyrrolidines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C115647:eletriptan; D018170:Sumatriptan