The in vivo activity of
GR205171, a novel, highly potent non-
peptide tachykinin NK1 receptor antagonist, has been investigated in the trigeminovascular system in order to assess its potential as an acute
therapy for
migraine headache. In anaesthetised rabbits,
GR205171 attenuated reductions in carotid arterial vascular resistance evoked by the
tachykinin NK1 receptor agonist,
substance P methyl ester (SPOMe), injected via the lingual artery (DR30 (i.e., the dose producing a dose-ratio of 30) = 0.4 microgram/kg, i.v.). In anaesthetised rats,
GR205171 (0.1 and 1 mg/kg, i.v.) produced a dose-dependent inhibition of
plasma protein extravasation (PPE) in dura mater, conjunctiva, eyelid and lip in response to electrical stimulation of the trigeminal ganglion. In anaesthetised guinea-pigs,
GR205171 (1.10 and 100 micrograms/kg, i.v.) inhibited, by up to approximately 60%, expression of c-fos in the trigeminal nucleus caudalis in response to electrical stimulation of the trigeminal ganglion. It is concluded that
GR205171 is a potent antagonist of NK1 receptor-mediated cranial vasodilatation, dural PPE and expression of c-fos in the trigeminal nucleus caudalis. Such a profile of action suggests that
GR205171 may have potential as a novel therapeutic agent in the treatment of
migraine headache.