THE ACTIVITY OF GR205171, A POTENT NONPEPTIDE TACHYKININ NK1 RECEPTORANTAGONIST, IN THE TRIGEMINOVASCULAR SYSTEM

The in vivo activity of GR205171, a novel, highly potent non-peptide t achykinin NK1 receptor antagonist, has been investigated in the trigem inovascular system in order to assess its potential as an acute therap y for migraine headache. In anaesthetised rabbits, GR205171 attenuated reductions in carotid arterial vascular resistance evoked by the tach ykinin NK1 receptor agonist, substance P methyl ester (SPOMe), injecte d via the lingual artery (DR(30) (i.e., the dose producing a dose-rati o of 30) = 0.4 mu g/kg, i.v.). In anaesthetised rats, GR205171 (0.1 an d 1 mg/kg, i.v.) produced a dose-dependent inhibition of plasma protei n extravasation (PPE) in dura mater, conjunctiva, eyelid and lip in re sponse to electrical stimulation of the trigeminal ganglion. In anaest hetised guinea-pigs, GR205171 (1, 10 and 100 mu g/kg, i.v.) inhibited, by up to approximately 60%, expression of c-fos in the trigeminal nuc leus 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 sug gests that GR205171 may have potential as a novel therapeutic agent in the treatment of migraine headache. (C) 1997 Elsevier Science B.V.