The pharmacology of GR203040, a novel, potent and selective non-peptide tachykinin NK1 receptor antagonist.

1. The in vitro and in vivo pharmacology of GR203040 ((2S, 3S)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), a novel, highly potent and selective non-peptide tachykinin NK1 receptor antagonist, was investigated in the present study. 2. GR203040 potently inhibited [3H]-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 (pKi values of 10.3, 10.5, 10.1 and 10.1 respectively). GR203040 had lower affinity at rat NK1 receptors (pKi = 8.6) and little affinity for human NK2 receptors (pKi < 5.0) in CHO cells and NK3 receptors in guinea-pig cortex (pKi < 6.0). With the exception of the histamine H1 receptor (pIC50 = 7.5). GR203040 had little affinity (pIC50 < 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 (pIC50 values < 4.0). GR203040 produced only weak antagonism of Ca(2+)-evoked contractions of rat isolated portal vein (pKn = 4.1). The enantiomer of GR203040, GR205608 (2R, 3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), had 10,000 fold lower affinity at the human NK1 receptor expressed in CHO cells (pKi = 6.3). 3. In gerbil ex vivo binding experiments, GR203040 produced a dose-dependent inhibition of the binding of [3H]-substance P to cerebral cortical membranes (ED50 = 15 micrograms kg-1 s.c. and 0.42 mg kg-1 p.o.). At 10 micrograms kg-1 s.c., the inhibition of [3H]-substance P binding was maintained for > 6 h. In the rat, GR203040 was less potent (ED50 = 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 pKB 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 (DR10 (i.e. the dose producing a dose-ratio of 10) = 1.1 micrograms kg-1, i.v.). At a dose 20 fold greater than its DR10 value (i.e. 22 micrograms 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 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.     

A comparison of the pharmacological and mechanical properties in vitro of large and small pulmonary arteries of the rat.

1. The mechanical and pharmacological properties of small pulmonary arteries (100-300 microns normalized lumen diameter) were directly compared with those of the left main pulmonary artery (1-2 mm) from the rat. The active and passive length-tension characteristics and responses to a variety of agonists and antagonists were dependent on arterial diameter. 2. Maximum contractile function was obtained in both groups of vessels when stretched so as to give an equivalent transmural pressure of 30 mmHg. This is substantially lower than that found for systemic vessels, and reflects the normal low pulmonary arterial pressure. 3. Noradrenaline was a powerful vasoconstrictor in large but not small pulmonary arteries (P less than 0.001). In contrast, bradykinin produced a significantly greater response in the small arteries (P less than 0.001). In comparison with large pulmonary arteries, small arteries were more sensitive to noradrenaline (P less than 0.05) and 5-hydroxytryptamine (P less than 0.001), less sensitive to endothelin-1 (P less than 0.001) and had the same sensitivity to prostaglandin F2 alpha. 4. The mechanism that maintains the low arterial tone of the pulmonary circulation is unknown, but it may involve the release of relaxing factors from the endothelium. In this preparation, basal resting tone could not be demonstrated in either large or small arteries. 5. Acetylcholine-induced relaxation of pre-contracted pulmonary arteries was reduced or absent in the small artery, despite histological evidence of an intact endothelium. In large arteries pre-contracted with prostaglandin F2 alpha, acetylcholine (100 mumol/l) caused 88.2% relaxation compared with 25.2% in the small artery.(ABSTRACT TRUNCATED AT 250 WORDS)     

A markedly diminished pleiotropic response to phenobarbital and structurally-related xenobiotics in Zucker rats in comparison with F344/NCr or DA rats.

Phenobarbital (PB) and certain structurally-related compounds induce a variety of hepatic drug-metabolizing enzymes in many strains of rats. Thus, following administration of PB (300, 500 ppm), barbital (BB, 1500 ppm) or 5-ethyl-5-phenylhydantoin (EPH, 500 ppm), CYP2B1-mediated benzyloxyresorufin O-dealkylase activity and epoxide hydrolase activity were profoundly induced in female DA and F344/NCr rats. In contrast, outbred female lean and obese Zucker rats showed markedly reduced CYP2B1 responses (less than 15% and less than 5% of those observed in the female DA or F344/NCr rat) to PB (doses less than or equal to 300 ppm), BB (1500 ppm) or EPH (500 ppm). In parallel studies, profound increases in RNA levels coding for CYP2B1, glutathione S-transferases Ya/Yc (alpha subclass), or epoxide hydrolase were detected in the female F344/NCr rat following treatment with PB (300 ppm), BB (1500 ppm) or EPH (500 ppm). In contrast, lean Zucker rats showed a strong response only to the highest dose of PB (500 ppm), implying that the diminished response in the Zucker rats may occur at some pretranslational level. Similar studies with lower doses of PB, EPH or BB in male lean Zucker rats showed a decreased response, relative to that in male F344/NCr rats. However, this insensitivity was not as profound as that observed in the female Zucker rats. In fact, the response to PB-type inducers in male or female Zucker rats is probably most clearly explained as a shift of the dose-response curve sharply to the right (decreased responsiveness, compared to F344/NCr or DA rats of the same sex). This decreased responsiveness of female lean Zucker rats to induction of CYP2B1, relative to that of F344/NCr rats, was also observed with the structurally-diverse PB-type inducers clonazepam, clotrimazole and 2-hexanone. In contrast, the female Zucker rat (obese or lean) displayed a pronounced response to induction of CYP1A-mediated ethoxyresorufin O-deethylase activity by beta-naphthoflavone, a prototype inducer of CYP1A1 and CYP1A2. The Zucker rat would thus appear to represent a potentially exploitable genetic model for examining the mechanism of enzyme induction by the myriad xenobiotics which induce a PB-type response.     

Exercise induced vasodepressor syncope.

Five cases of exercise induced pure vasodepressor syncope in patients without significant structural heart disease are reported. Hypotension and symptoms of syncope or pre-syncope were induced by treadmill exercise testing and in each case limited exercise performance. Evidence of inappropriate peripheral vasodilation, probably as a consequence of ventricular mechanoreceptor stimulation, was shown in all five patients. Head up tilt testing resulted in hypotension in four patients and isoprenaline infusion in the supine position resulted in hypotension in the fifth. These patients had a new condition of exercise induced neurally mediated (vasodepressor) syncope without appreciable structural cardiac abnormalities.     

Balloon dilatation of the aortic valve: limited success and early restenosis.

Balloon dilatation of the aortic valve was attempted 16 times in 15 patients with severe aortic stenosis. None died but one had a transient stroke after the procedure. At dilatation the gradient across the aortic valve was reduced by greater than 30% in 69% of patients and the Gorlin valve area (calculated in 7/15 patients) increased by 30% in half. But a comparison of Doppler gradients measured before and one to two days after dilatation in 11 patients showed a greater than 30% reduction in the simultaneously measured gradient in only four. Doppler gradient was the most accurate predictor of symptomatic benefit and a fall in Doppler gradient persisted mainly in patients whose peak to peak gradient fell by at least 40% at the time of the procedure. Balloon dilatation of the aortic valve is a relatively safe procedure but it is less successful than previous reports suggest, perhaps because of early restenosis. Some forms of aortic stenosis may be more amenable to this procedure than others.     

Ureteral obstruction following aortobifemoral bypass: management by endoscopic balloon dilation.

A 71-year-old man presented with left hydronephrosis 1 year after aortofemoral bypass. Hydronephrosis was due to extrinsic compression of the ureter between the graft anteriorly and the native iliac artery. Treatment by endoscopic transluminal balloon dilation resulted in complete resolution of the hydronephrosis.     

Alpha thalassaemia hydrops fetalis in the UK: the importance of screening pregnant women of Chinese, other South East Asian and Mediterranean extraction for alpha thalassaemia trait.

OBJECTIVE: Alpha zero (alpha 0 or alpha-1) thalassaemia is an important genetic risk for women originating from Hong Kong, Singapore, Vietnam, Thailand, the Philippines or South China. Cypriots are also at risk. Carriers of alpha zero thalassaemia trait can be detected by routine haemoglobinopathy screening. When a couple are both carriers, in each pregnancy there is a 25% risk that the fetus will have alpha thalassaemia hydrops fetalis; this is fatal for the fetus and carries serious obstetric and psychological risks for the mother. Most informed couples at risk request prenatal diagnosis and selective abortion. This study investigates the effectiveness of screening, counselling and prenatal diagnosis for alpha thalassaemia hydrops fetalis in the UK. DESIGN: Retrospective analysis of the notes. SUBJECTS: 18 couples attending University College Hospital London for prenatal diagnosis of alpha thalassaemia hydrops fetalis since 1982. RESULTS: The study shows underdiagnosis of both alpha zero thalassaemia trait and alpha thalassaemia hydrops fetalis leading to avoidable stillbirths and complications in pregnancy. CONCLUSION: We recommend early screening for alpha zero thalassaemia trait for all women of Southeast Asian or eastern Mediterranean origin and the offer of prenatal diagnosis when indicated. The diagnosis of alpha thalassaemia hydrops fetalis should be considered in women of the relevant ethnic origin who have a stillbirth, neonatal death, abnormal ultrasound findings at fetal anomaly scanning (especially a large placenta), or who develop pre-eclampsia.     

Discovery of potent and selective inhibitors of procollagen C-proteinase for the treatment of fibrotic disorders

Introduction   Fibrosis is a component of many tissue pathologies leading to loss of normal tissue function, primarily due to excessive collagen deposition. Collagen is deposited following cleavage of the C- and N- terminal peptides from the pro-collagen molecule. The cleavage of the globular C-peptide by PCP reduces solubility of the fibrillar collagen molecule, resulting in deposition of insoluble collagen. Increased insoluble collagen deposition is a feature of all organ fibroses, with inhibition of this process, a key potential anti-fibrotic mechanism. The aim of this work was to discover potent and selective PCP inhibitors as experimental, topically applied, anti-fibrotic drugs for clinical evaluation.
Materials and methods   PCP was cloned from human osteosarcoma cells and enzymatic activity demonstrated using a PCP-specific peptide cleavage assay. Activities were confirmed by measuring cleavage of [³H]C-peptide from type-I pro-collagen. A cell-based fibroplasias model was employed to demonstrate compound efficacy using collagen deposition, liberated C-peptide and histological endpoints. The activities of PCP inhibitors in fibroblast and epithelial in vitro cell proliferation and migration assays, and selectivity vs. a panel of MMPs were also determined.
Discussion   In summary, we have identified and characterized potent and selective inhibitors of PCP for progression to clinical studies for investigation as a treatment paradigm for fibrotic disease.  

  Results     

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