Investigations with GMC2021 in experimental models predictive of antimigraine activity and coronary side-effect potential.
Several acutely acting antimigraine drugs, including sumatriptan and other second generation 5-HT1D receptor agonists, have the ability to constrict porcine carotid 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 GMC2021 (3-[2-(dimethylanimo)ethyl]-5-[(trifluoromethyl)sulfonyl]oxy][1 H]indole oxalate, a close analogue of sumatriptan. GMC2021 (30, 100, 300 and 1000 micrograms.kg-1, i.v.) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow to the skin and ears was moderately increased. The mean +/- S.E.M. dose of GMC2021 eliciting a 50% decrease (ED50) in the porcine carotid arteriovenous anastomotic blood flow was found to be 1.1 +/- 0.3 mumol.kg-1 and the highest dose (1000 micrograms.kg-1) produced a 67 +/- 4% reduction. The carotid haemodynamic effects of GMC2021 were reduced by the selective 5-HT1D receptor antagonist, GR127935 (N-[methoxy-3-(4-methyl-1- piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1 , 1-biphenyl]-4-carboxamide hydrochloride), which completely antagonizes porcine carotid haemodynamic responses to sumatriptan (ED50: 0.16 mumol.kg-1, i.v.). Compared to sumatriptan (pD2: 6.12 +/- 0.15; Emax: 31.3 +/- 12.3% of contractions to 100 mM K+), GMC2021 was less potent in constricting the human isolated coronary artery (pD2: 5.45 +/- 0.2; Emax: 21.0 +/- 4.8% of contractions to 100 mM K+). The above results suggest that GMC2021 constricts carotid arteriovenous anastomoses partly by a 5-HT1D receptor and partly by another, probably novel, receptor and that GMC2021 should be able to abort migraine headaches in patients, with perhaps a less propensity for coronary side effects.
Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, Netherlands. Saxena@Farma.Fgg.Eur.NL
P R
PR
Saxena
P
P
De Vries
J P
JP
Heiligers
A
A
Maassen VanDenBrink
W A
WA
Bax
T
T
Barf
H
H
Wikström
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008881:Migraine Disorders / Q000188:drug therapy*; D018170:Sumatriptan / Q000031:analogs & derivatives* / Q000494:pharmacology; D013552:Swine; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
C103480:GMC 2021; D014662:Vasoconstrictor Agents; D018170:Sumatriptan