THE PHARMACOLOGY OF GR203040, A NOVEL, POTENT AND SELECTIVE NONPEPTIDE TACHYKININ NK1 RECEPTOR ANTAGONIST

1 The in vitro and in vivo pharmacology of GR203040 ((2S, azol-1-yl-be nzyl-(2-phenyl-piperidin-3-yl)-amine), a novel, highly potent and sele ctive 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 (CH O) and U373 MG astrocytoma cells, and NK1 receptors in ferret and gerb il cortex (pK(i) values of 10.3, 10.5, 10.1 and 10.1 respectively). GR 203040 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 rece ptors in guinea-pig cortex (pK(i)<6.0). With the exception of the hist amine H-1 receptor (pIC(50) = 7.5), GR203040 had little affinity (pIC( 50)<6.0) at all non-NK1 receptors and ion channels examined. Furthermo re, 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 contraction s of rat isolated portal vein (pK(B) = 4.1). The enantiomer of GR20304 0, GR205608 ((2R, trazol-1-yl-benzyl-(2-phenyl-piperidin-3-yl)-amine h ad 10,000 fold lower affinity at the human NK1 receptor expressed in C HO cells (pK(i)=6.3). 3 In gerbil ex vivo binding experiments, GR20304 0 produced a dose-dependent inhibition of the binding of [H-3]-substan ce 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]-su bstance P binding was maintained for >6 h. In the rat, GR203040 was le ss potent (ED(50)=15.4 mg kg(-1) s.c.) probably reflecting, at least i n part, its lower affinity at the rat NK1 receptor. 4 In guinea-pig is olated ileum and dog isolated middle cerebral and basilar arteries, GR 203040 produced a rightward displacement of the concentration-effect c urves to substance P methyl ester (SPOMe) with suppression of the maxi mum agonist response (apparent pK(B) values of 11.9, 11.2 and 11.1 res pectively). 5 In anaesthetized rabbits, GR203040 antagonized reduction s in carotid arterial vascular resistance evoked by SPOMe, injected vi a 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 inhibiti on of plasma protein extravasation in dura mater, conjunctiva, eyelid and lip in response to electrical stimulation of the trigeminal gangli on. 7 It is concluded that GR203040 is one of the most potent and sele ctive NK1 receptor antagonists yet described, and as such, has conside rable potential as a pharmacological tool to characterize the physiolo gical and pathological roles of substance P and NK1 receptors. GR20304 0 may also have potential as a novel therapeutic agent for the treatme nt of conditions such as migraine, emesis and pain.