The activity of GR205171, a potent non-peptide tachykinin NK 1 receptor antagonist, in the trigeminovascular system

Abstract

The in vivo activity of GR205171, a novel, highly potent non-peptide tachykinin NK 1 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 NK 1 receptor agonist, substance P methyl ester (SPOMe), injected via the lingual artery (DR 30 (i.e., the dose producing a dose-ratio of 30)=0.4 μg/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 μg/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 NK 1 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.