title: Effects of avitriptan, a new 5-HT 1B/1D receptor agonist, in experimental models predictive of antimigraine activity and coronary side-effect potential.
abstract: Several acutely acting antimigraine drugs, including ergotamine and sumatriptan, have the ability to constrict porcine arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of avitriptan (BMS-180048; 3-[3-[4-(5-methoxy-4-pyrimidinyl)-l-piperazinyl[propyl]-N-methyl-l H-indole-5-methane-sulfonamide monofumarate), a new 5-HT 1B/1D receptor agonist. In anaesthetized pigs, avitriptan (10, 30, 100 and 300 micrograms.kg-1) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow was increased. The mean +/- SEM i.v. dose of avitriptan eliciting a 50% decrease (ED50) in the porcine carotid arteriovenous anastomotic blood flow was calculated to be 76 +/- 23 micrograms.kg-1 (132 +/- 40 nmol.kg-1) and the highest dose (300 micrograms.kg-1) produced a 72 +/- 4% reduction. In recent comparative experiments (DeVries et al. 1996), the mean +/- SEM ED50 (i.v.) of sumatriptan in decreasing carotid arteriovenous anastomotic blood flow was 63 +/- 17 micrograms.kg-1 (158 +/- 43 nmol.kg-1), with a reduction of 76 +/- 4% by 300 micrograms.kg-1, i.v. Both avitriptan (pD2; 7.39 +/- 0.09; Emax: 13.0 +/- 4.5% of the contraction to 100 mM K+) and sumatriptan (pD2: 6.33 +/- 0.09; Emax: 15.5 +/- 2.3% of the contraction to 100 mM K+) contracted the human isolated coronary artery. The above results suggest that avitriptan should be able to abort migraine headaches in patients, but may exhibit sumatriptan-like effects on coronary arteries. Initial clinical studies have demonstrated the therapeutic action of the drug in acute migraine.
authors.affiliation: Department of Pharmacology, Dutch Migraine Research Group, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, The Netherlands.
authors.forename: P R
authors.initials: PR
authors.lastname: Saxena
authors.forename: P
authors.initials: P
authors.lastname: De Vries
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: J P
authors.initials: JP
authors.lastname: Heiligers
authors.forename: A
authors.initials: A
authors.lastname: Maassen vandenBrink
authors.forename: W A
authors.initials: WA
authors.lastname: Bax
authors.forename: F D
authors.initials: FD
authors.lastname: Yocca
mesh_terms: D000818:Animals; D001163:Arteriovenous Anastomosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D006257:Head / Q000033:anatomy & histology / Q000098:blood supply; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology*; D008881:Migraine Disorders / Q000188:drug therapy; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000494:pharmacology*; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology; D013552:Swine; D014363:Tryptamines; D014662:Vasoconstrictor Agents / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C470302:HTR1B protein, human; D007211:Indoles; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D014363:Tryptamines; D014662:Vasoconstrictor Agents; C103231:avitriptan; D018170:Sumatriptan