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The NK1 receptor antagonist CP-99,994 inhibits emesis in the ferret
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37
APRIL SUPPLEMENT
(SAP) and heart rate (HR) in the absence and presence of NG-nitro-L-arginine (L-NNA, i.v. 3 mg/kg). ET-l and -3 injected i.v. at doses of 0.1, 0.3 and 1 nrnol/kg evoked transient dose-dependent falls in SAP with corresponding increases in HR, similar between WKY and SHRSP. The initial depressor effects of ET-l and -3 were followed by dose-dependent sustained rises in SAP with concomitant decreasesin HR both in WKY and SHRSP. There was no significant difference in the pressor effects of ET- 1 between the 2 rat strains, whereas the reduction in HR after 1 mnol/kg ET-l was more markedly in WKY compared to SHRSP. The pressor effect of ET-3 (1 mnol/kg) was greater in SHRSP compared to WKY without a significant difference in the bradycardic responses. In the presence of L-NNA the hypotensive and pressor responses caused by the administrations of ET-l and -3 (1 nmol/kg) were enhanced. Endothelins participate in the regulation of peripheral circulation more positively in SHRSP than in WKY through NO-production and baroreflex systems.
P7/6 The NK, Receptor Antagonist CP-99,994 Inhibits Emesis in the Ferret F. D. Tattersall, W. Rycroft, R. G. Hill and R. J. Hargreaves Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, UK 5-HT, receptor antagonists inhibit emesis induced by cisplatin but not apomorphine. Since substance P, released by cytotoxic agents, may induce emesis and was excitatory when applied in vivo to cells in the region of the area postrema and nucleus tractus solitariusl we examined a neurokinin, (NK,) receptor antagonist CP-99,994 and its inactive enantiomer CP- 100,263 on the retching and vomiting induced by cisplatin and apomorphine in the ferret.
Cisplatin studies Male ferrets (1 .l-1.8 kg) were injected iv. with CP99,994 (0.3-3 mgkg), CP-100,263 (3 mgkg) or water (1 ml/kg) followed 3 min later by cisplatin (10 mgkg i.v.). Animals were observed for the 4 h after cisplatin injection.
Apomorphine studies Male ferrets (1.2-1.8 kg) were injected i.p. with CP99,994 (0.3,l or 3 mg/kg), CP-100,263 (3 mg/kg) orwater (1 ml/kg) followed 30 min later by apomorphine (0.25 mgkg s.c.). Animals were observed for 30 mm after apomorphine injection.
Results CP-99,994 (l-3 mg/kg) reduced the retching and vomiting induced by both cisplatin and apomorphine. CP100,263 (3 m&kg) was ineffective.
NK, receptor antagonists may give broader protection against emetogenic stimuli refractory to treatment with 5I-IT, receptor antagonists. 1. Anchews, P. L. R., Rapeport W. G. and Sanger, G. J. Neurophannacology of emesis induced by anti-cancer therapy. Trends Pharmacol. Sci. 1988; 9: 334-341.
P7/7 Different Behavioral Prollles of Specific Tachykinin Receptor Agonists in Guineapigs 0. Piot, J. Betschart, I. Grail, S. Ravard, C. Garret and J.-C. Blanchard Rhone-Poulenc Rorer SA, CRVA, Vitry-sur-Seine, France Evidence of homologies between guinea-pig and human tachykinin receptors led us to evaluate the activity of septide and set&tide, selective agonists for the NK, and NK, receptors, respectively, injected i.c.v. in guinea-pigs. Septide at 0.63-2.5 pg significantly increased locomotor activity and at 2.5 pg induced wet dog shakes and grooming. The new non-peptidic selective NK, antagonist RPR 100893, having high affinity in guinea-pig brain, significantly antagonized these responses when given by S.C.or oral route (10 mgkg). Interestingly, locomotor hyperactivity induced by septide was attenuated by haloperidol (0.5 mgkg s.c.), supporting the hypothesis of a dopaminergic mediation. Se&tide (0.32-l .25 ug) elicited wet dog shakes, as has been described for rodents. RPR 100893 ( 10 m&g s.c.) did not block this behavior. Se&tide neither modified locomotor activity (1 pg) nor induced grooming (up to 5 pg). Thus, the stimulation of the NK, tachykinin receptor could preferentially result in 5-HTmediated behavior, which has been reported to be blocked by 5-HT, antagonists in rodents. Thus, behavioral studies with guinea-pigs appear to be useful for analyzing humanspecific tachykinin receptor antagonists.
P7/8 CGP 49823, a Novel, Non-peptidic NK-1 Receptor Antagonist: in vitro Pharmacology K. Hauser, J. Heid, L. Criscione, F. Brugger, S. Ofner, S. Veenstra and W. Schilling Research Department, Pharmaceuticals Division, Ciba-Geigy Ltd, Basel, Switzerland CGP 49823, (2R, 4S)-2-Benzyl-l-(3,5dimethylbenzoyl)-N-[(4_quinolinyl) methyl]-4-piperidineamine, is a novel antagonist of substance P (SP). The compound inhibited 3H-SP binding to bovine retina membranes with an IC,, of 12 nM. Antagonism of the human NK, receptor was shown by the inhibition of SP-induced inositol monophosphate production in U-373MG human astrocytoma cells with an IC,, of 13 nM. CGP 49823 inhibited the contractile effects of SP in the rabbit vena cava with
37
APRIL SUPPLEMENT
(SAP) and heart rate (HR) in the absence and presence of NG-nitro-L-arginine (L-NNA, i.v. 3 mg/kg). ET-l and -3 injected i.v. at doses of 0.1, 0.3 and 1 nrnol/kg evoked transient dose-dependent falls in SAP with corresponding increases in HR, similar between WKY and SHRSP. The initial depressor effects of ET-l and -3 were followed by dose-dependent sustained rises in SAP with concomitant decreasesin HR both in WKY and SHRSP. There was no significant difference in the pressor effects of ET- 1 between the 2 rat strains, whereas the reduction in HR after 1 mnol/kg ET-l was more markedly in WKY compared to SHRSP. The pressor effect of ET-3 (1 mnol/kg) was greater in SHRSP compared to WKY without a significant difference in the bradycardic responses. In the presence of L-NNA the hypotensive and pressor responses caused by the administrations of ET-l and -3 (1 nmol/kg) were enhanced. Endothelins participate in the regulation of peripheral circulation more positively in SHRSP than in WKY through NO-production and baroreflex systems.
P7/6 The NK, Receptor Antagonist CP-99,994 Inhibits Emesis in the Ferret F. D. Tattersall, W. Rycroft, R. G. Hill and R. J. Hargreaves Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, UK 5-HT, receptor antagonists inhibit emesis induced by cisplatin but not apomorphine. Since substance P, released by cytotoxic agents, may induce emesis and was excitatory when applied in vivo to cells in the region of the area postrema and nucleus tractus solitariusl we examined a neurokinin, (NK,) receptor antagonist CP-99,994 and its inactive enantiomer CP- 100,263 on the retching and vomiting induced by cisplatin and apomorphine in the ferret.
Cisplatin studies Male ferrets (1 .l-1.8 kg) were injected iv. with CP99,994 (0.3-3 mgkg), CP-100,263 (3 mgkg) or water (1 ml/kg) followed 3 min later by cisplatin (10 mgkg i.v.). Animals were observed for the 4 h after cisplatin injection.
Apomorphine studies Male ferrets (1.2-1.8 kg) were injected i.p. with CP99,994 (0.3,l or 3 mg/kg), CP-100,263 (3 mg/kg) orwater (1 ml/kg) followed 30 min later by apomorphine (0.25 mgkg s.c.). Animals were observed for 30 mm after apomorphine injection.
Results CP-99,994 (l-3 mg/kg) reduced the retching and vomiting induced by both cisplatin and apomorphine. CP100,263 (3 m&kg) was ineffective.
NK, receptor antagonists may give broader protection against emetogenic stimuli refractory to treatment with 5I-IT, receptor antagonists. 1. Anchews, P. L. R., Rapeport W. G. and Sanger, G. J. Neurophannacology of emesis induced by anti-cancer therapy. Trends Pharmacol. Sci. 1988; 9: 334-341.
P7/7 Different Behavioral Prollles of Specific Tachykinin Receptor Agonists in Guineapigs 0. Piot, J. Betschart, I. Grail, S. Ravard, C. Garret and J.-C. Blanchard Rhone-Poulenc Rorer SA, CRVA, Vitry-sur-Seine, France Evidence of homologies between guinea-pig and human tachykinin receptors led us to evaluate the activity of septide and set&tide, selective agonists for the NK, and NK, receptors, respectively, injected i.c.v. in guinea-pigs. Septide at 0.63-2.5 pg significantly increased locomotor activity and at 2.5 pg induced wet dog shakes and grooming. The new non-peptidic selective NK, antagonist RPR 100893, having high affinity in guinea-pig brain, significantly antagonized these responses when given by S.C.or oral route (10 mgkg). Interestingly, locomotor hyperactivity induced by septide was attenuated by haloperidol (0.5 mgkg s.c.), supporting the hypothesis of a dopaminergic mediation. Se&tide (0.32-l .25 ug) elicited wet dog shakes, as has been described for rodents. RPR 100893 ( 10 m&g s.c.) did not block this behavior. Se&tide neither modified locomotor activity (1 pg) nor induced grooming (up to 5 pg). Thus, the stimulation of the NK, tachykinin receptor could preferentially result in 5-HTmediated behavior, which has been reported to be blocked by 5-HT, antagonists in rodents. Thus, behavioral studies with guinea-pigs appear to be useful for analyzing humanspecific tachykinin receptor antagonists.
P7/8 CGP 49823, a Novel, Non-peptidic NK-1 Receptor Antagonist: in vitro Pharmacology K. Hauser, J. Heid, L. Criscione, F. Brugger, S. Ofner, S. Veenstra and W. Schilling Research Department, Pharmaceuticals Division, Ciba-Geigy Ltd, Basel, Switzerland CGP 49823, (2R, 4S)-2-Benzyl-l-(3,5dimethylbenzoyl)-N-[(4_quinolinyl) methyl]-4-piperidineamine, is a novel antagonist of substance P (SP). The compound inhibited 3H-SP binding to bovine retina membranes with an IC,, of 12 nM. Antagonism of the human NK, receptor was shown by the inhibition of SP-induced inositol monophosphate production in U-373MG human astrocytoma cells with an IC,, of 13 nM. CGP 49823 inhibited the contractile effects of SP in the rabbit vena cava with