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The pharmacology of GR203040, a novel, potent and selective non‐peptide tachykinin NK 1 receptor antagonist
Author(s) -
Beattie D.T.,
Beresford I.J.M.,
Connor H.E.,
Marshall F.H.,
Hawcock A.B.,
Hagan R.M.,
Bowers J.,
Birch P.J.,
Ward P.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15117.x
Subject(s) - tachykinin receptor , receptor , chemistry , pharmacology , substance p , medicine , biology , endocrinology , biochemistry , neuropeptide
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 NK 1 receptor antagonist, was investigated in the present study. 2 GR203040 potently inhibited [ 3 H]‐substance P binding to human NK 1 receptors expressed in Chinese hamster ovary (CHO) and U373 MG astrocytoma cells, and NK 1 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 NK 1 receptors (pK i = 8.6) and little affinity for human NK 2 receptors (pK i < 5.0) in CHO cells and NK 3 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‐NK 1 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 Ca 2+ ‐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 NK 1 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 [ 3 H]‐substance P to cerebral cortical membranes (ED 50 = 15 μg kg −1 s.c. and 0.42 mg kg −1 p.o.). At 10 μg kg −1 s.c., the inhibition of [ 3 H]‐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 NK 1 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 μg kg −1 , i.v.). At a dose 20 fold greater than its DR 10 value (i.e. 22 μg kg −1 , i.v.), significant antagonism 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 NK 1 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 NK 1 receptors. GR203040 may also have potential as a novel therapeutic agent for the treatment of conditions such as migraine, emesis and pain.