Naratriptan: biological profile in animal models relevant to migraine.
The biological profile of naratriptan (N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethane-sulphonamide), a novel 5HT1B/1D receptor agonist, was investigated in a variety of experimental models of relevance to migraine. Naratriptan has high affinity for human recombinant 5HT1B and 5HT1D receptors (pKi = 8.7 +/- 0.03 and 8.3 +/- 0.1, respectively) and causes contractions of dog isolated basilar and middle cerebral artery (EC50 values of 0.11 and 0.07 microM, respectively). Naratriptan causes small contractions of human isolated coronary arteries (EC50 value of 0.17 microM; maximum contraction equivalent to 33% of 5HT maximum). In anaesthetized dogs, naratriptan causes selective vasoconstriction of the carotid arterial bed (CD50 dose = 19 +/- 3 micrograms kg-1) and, in anaesthetized rats, naratriptan selectively inhibits neurogenic plasma protein extravasation in the dura (ID50 = 4.1 micrograms kg-1). In a variety of antinociceptive tests, naratriptan has no effect even at high doses. In conscious rats and dogs, naratriptan has high oral bioavailability (71% and 95%, respectively). The data show that naratriptan is a selective agonist at 5HT1B/1D receptors, with a pharmacological profile very similar to that of sumatriptan, albeit 2-3 fold more potent. These observations, coupled with high oral bioavailability in animals, suggest that naratriptan has the profile of an orally effective anti-migraine drug.
Connor
H E
HE
Glaxo Wellcome R&D Ltd, Stevenage, Herts, UK.
Feniuk
W
W
Beattie
D T
DT
North
P C
PC
Oxford
A W
AW
Saynor
D A
DA
Humphrey
P P
PP
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D018170:Sumatriptan / Q000031:analogs & derivatives* / Q000494:pharmacology; D014363:Tryptamines
D007211:Indoles; D010880:Piperidines; D014363:Tryptamines; D018170:Sumatriptan; C106783:naratriptan