1 The in vitro and in vivo pharmacology of GR203040 ((2S, 3S)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-yl)-amine), a novel, highly potent and selective non-peptide tachykinin NK1 receptor antagonist, was investigated in the present study. 2 GR203040 potently inhibited [H-3]-substance P binding to human NK1 receptors expressed in Chinese hamster ovary (CHO) and U373 MG astrocytoma cells, and NK1 receptors in ferret and gerbil cortex (pK(i) values of 10.3, 10.5, 10.1 and 10.1 respectively). GR203040 had lower affinity at rat NK1 receptors (pK(i)=8.6) and little affinity for human NK2 receptors (pK(i)<5.0) in CHO cells and NK3 receptors in guinea-pig cortex (pK(i)<6.0). With the exception of the histamine H-1 receptor (pIC(50) = 7.5), GR203040 had little affinity (pIC(50)<6.0) at all non-NK1 receptors and ion channels examined. Furthermore, GR203040 produced only weak inhibition of Na+ currents in SH-SY5Y neuroblastoma and superior cervical ganglion cells (pIC(50) values < 4.0). GR203040 produced only weak antagonism of Ca2+-evoked contractions of rat isolated portal vein (pK(B) = 4.1). The enantiomer of GR203040, GR205608 ((2R, 3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-yl)-amine had 10,000 fold lower affinity at the human NK1 receptor expressed in CHO cells (pK(i)=6.3). 3 In gerbil ex vivo binding experiments, GR203040 produced a dose-dependent inhibition of the binding of [H-3]-substance P to cerebral cortical membranes (ED(50)=15 mu g kg(-1) s.c. and 0.42 mg kg(-1) p.o.). At 10 mu g kg(-1) s.c., the inhibition of [H-3]-substance P binding was maintained for >6 h. In the rat, GR203040 was less potent (ED(50)=15.4 mg kg(-1) s.c.) probably reflecting, at least in part, its lower affinity at the rat NK1 receptor. 4 In guinea-pig isolated ileum and dog isolated middle cerebral and basilar arteries, GR203040 produced a rightward displacement of the concentration-effect curves to substance P methyl ester (SPOMe) with suppression of the maximum agonist response (apparent pK(B) values of 11.9, 11.2 and 11.1 respectively). 5 In anaesthetized rabbits, GR203040 antagonized reductions in carotid arterial vascular resistance evoked by SPOMe, injected via the lingual artery (DR(10) (i.e. the dose producing a dose-ratio of 10)=1.1 mu g kg(-1), i.v.). At a dose 20 fold greater than its DR(10) value (i.e. 22 mu g kg(-1), i.v.), significantant agonism was evident more than 2 h after GR203040 administration. 6 In anaesthetized rats, GR203040 (3 and 10 mg kg(-1), i.v.) produced a dose-dependent inhibition of plasma protein extravasation in dura mater, conjunctiva, eyelid and lip in response to electrical stimulation of the trigeminal ganglion. 7 It is concluded that GR203040 is one of the most potent and selective NK1 receptor antagonists yet described, and as such, has considerable potential as a pharmacological tool to characterize the physiological and pathological roles of substance P and NK1 receptors. GR203040 may also have potential as a novel therapeutic agent for the treatment of conditions such as migraine, emesis and pain.
