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P Vilain

Publications and source records attributed to P Vilain.

15 recordsLinked to original sources
PubMed1997

Biochemical and pharmacological activities of SR 144190, a new potent non-peptide tachykinin NK2 receptor antagonist.

(R)-3-(1-[2-(4-benzoyl-2-(3,4-difluorophenyl)-morpholin-2-yl)- ethyl]-4-phenylpiperidin-4-yl)-1-dimethylurea (SR 144190) is a new non-peptide antagonist of tachykinin NK2 receptors. SR 144190 potently and selectively inhibited neurokinin A binding to NK2 receptors from various species, including humans. In in vitro functional assays, it was a potent, selective and competitive antagonist of NK2 receptors with apparent affinities (pA2 values) between 9.08 and 10.10. In vivo, SR 144190 blocked [Nle10]neurokinin A-(4-10)-induced bronchoconstriction in guinea pigs (ID50 = 21 micrograms kg-1 i.v. and 250 micrograms kg-1 i.d.) and [beta Ala8]neurokinin A-(4-10)-induced urinary bladder contraction in rats (ID50 = 11 micrograms kg-1 i.v. and 190 micrograms kg-1 i.d.). It prevented citric acid-induced cough and airway hyperresponsiveness to acetylcholine in guinea pigs (1 mg kg-1 i.p.) as well as castor oil-induced diarrhoea in rats (0.01-10 micrograms kg-1 s.c. or p.o). Finally, it blocked the turning behaviour induced by intrastriatal injections of [Nle10]neurokinin A-(4-10) in mice (ID50 = 3 micrograms kg-1 i.v. and 16 micrograms kg-1 p.o.).

Animals↗
PubMed1997

Tachykinin-induced contractions of the guinea pig ileum longitudinal smooth muscle: tonic and phasic muscular activities.

In vitro tachykinin-induced contractions of guinea pig ileum longitudinal smooth muscle were investigated under isometric conditions by using selective agonists ([Sar9,Met(O2)11]substance P, [Nle10]neurokinin A-(4-10), senktide) and antagonists (SR 140333, SR 48968, SR 142801), respectively, for the tachykinin NK1, NK2, and NK3 receptors. [Sar9,Met(O2)11]Substance P (10 nM) induced a tonic contraction with superimposed phasic contractions. Both tonic and phasic muscular activities were completely abolished by SR 140333 (10 nM) and were not modified by SR 142801 (10 nM). SR 48968 (10 nM) and atropine (0.001 mM) did not modify the tonic muscular activity but inhibited the phasic muscular activity. [Nle10]Neurokinin A-(4-10) (10 nM) only caused a phasic contractile response that was inhibited by SR 48968. Atropine, SR 140333, and SR 142801 were without effect. Senktide (1 nM) induced combined tonic and phasic contractile responses. SR 142801 blocked the phasic and tonic muscular activities, whereas SR 48968 and SR 140333 were inactive. After addition of atropine, only tonic contractile response was abolished. These results showed fundamental differences in isometric tonic and phasic contractile responses of guinea pig ileum longitudinal smooth muscle to tachykinins.

Animals↗
PubMed1996

Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist.

SR 121463A, a potent and selective, orally active, nonpeptide vasopressin V2 receptor antagonist, has been characterized in several in vitro and in vivo models. This compound displayed highly competitive and selective affinity for V2 receptors in rat, bovine and human kidney (0.6 < or = Ki [nM] < or = 4.1). In this latter preparation, SR 121463A potently antagonized arginine vasopressin (AVP)-stimulated adenylyl cyclase activity (Ki = 0.26+/-0.04 nM) without any intrinsic agonistic effect. In autoradiographic experiments performed in rat kidney sections, SR 121463A displaced [3H]AVP labeling especially in the medullo-papillary region and confirmed that it is a suitable tool for mapping V2 receptors. In comparison, the nonpeptide V2 antagonist, OPC-31260, showed much lower affinity for animal and human renal V2 receptors and lower efficacy to inhibit vasopressin-stimulated adenylyl cyclase (Ki in the 10 nanomolar range). Moreover, OPC-31260 exhibited a poor V2 selectivity profile and can be considered as a V2/V1a ligand. In normally hydrated conscious rats, SR 121463A induced powerful aquaresis after intravenous (0.003-0.3 mg/kg) or oral (0.03-10 mg/kg) administration. The effect was dose-dependent and lasted about 6 hours at the dose of 3 mg/kg p.o. OPC-31260 had a similar aquaretic profile but with markedly lower oral efficacy. The action of SR 121463A was purely aquaretic with no changes in urine Na+ and K+ excretions unlike that of known diuretic agents such as furosemide or hydrochlorothiazide. In addition, no antidiuretic properties have been detected with SR 121463A in vasopressin-deficient Brattleboro rats. Thus, SR 121463A is the most potent and selective, orally active V2 antagonist yet described and could be a powerful tool for exploring V2 receptors and the therapeutical usefulness of V2 blocker aquaretic agents in water-retaining diseases.

Adenylyl Cyclases↗
PubMed1995

SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor.

SR 142801 is the first potent and selective non-peptide antagonist of the tachykinin NK3 receptor. It inhibited [MePhe7]NKB binding to its receptor from various species, including humans. SR 142801 was a competitive antagonist of [MePhe7]NKB-mediated contractions of guinea-pig ileum and inhibited the acetylcholine release following the activation of the guinea-pig ileum tachykinin NK3 receptor. In vivo, SR 142801 potently inhibited the turning behaviour induced by intrastriatal injection of senktide in gerbils, and appears as a powerful tool for investigation of the physiological and pathological role of NKB and its NK3 receptor.

Animals↗
PubMed1995

Effect of the two tachykinin antagonists, SR 48968 and SR 140333, on cough induced by citric acid in the unanaesthetized guinea pig.

It is now well-established that sensory nerves stimulation in the airway induces bronchoconstriction and inflammation, but also protective reflexes, such as coughing. These effects are mediated through the release of tachykinins (substance P and neurokinin A) and we have recently shown that SR 48968, a tachykinin NK2-receptor antagonist, inhibited cough induced by citric acid. In this paper, we have studied the effects of SR 48968 administered by aerosol. We have also investigated the effects of SR 140333, a tachykinin NK1-receptor antagonist, and the combination of both SR 48968 and SR140333 to determine whether tachykinin NK1 receptors are involved in cough. Finally, we have studied the combined effects of SR 48968 and salbutamol to find out whether the antitussive effect of SR 48968 is a consequence of the inhibition of bronchoconstriction. Unanaesthetized guinea-pigs were placed in a transparent chamber and exposed to an aerosol of citric acid (0.4 M). The number of coughs was counted by visual inspection and by determination of sounds and pressure variations in the chamber. By the aerosol route, SR 48968 was an efficient antitussive and 16 times more potent than codeine. SR 140333 (0.1-1 mg.kg-1 i.p.) did not exert any antitussive effect but it potentiated the maximal effect induced by SR 48968. Finally, salbutamol, in a dose (0.3 mg.kg-1) which inhibits bronchoconstriction, but not cough induced by citric acid, did not modify the antitussive effect of SR 48968.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1993

In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK1 receptor antagonist.

(S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)pip eridin-3- yl]ethyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (SR140333) is a new non-peptide antagonist of tachykinin NK1 receptors. SR140333 potently, selectively and competitively inhibited substance P binding to NK1 receptors from various animal species, including humans. In vitro, it was a potent antagonist in functional assays for NK1 receptors such as [Sar9,Met(O2)11]substance P-induced endothelium-dependent relaxation of rabbit pulmonary artery and contraction of guinea-pig ileum. Up to 1 microM, it had no effect in bioassays for NK2 ([beta Ala8]neurokinin A-induced contraction of endothelium-deprived rabbit pulmonary artery) and NK3 ([MePhe7]neurokinin B-induced contraction of rat portal vein) receptors. The antagonism exerted by SR140333 toward NK1 receptors was apparently non-competitive, with pD2' values (antagonism potency evaluated by the negative logarithm of the molar concentration of antagonist that produces a 50% reduction of the maximal response to the agonist) between 9.65 and 10.16 in the different assays. SR140333 also blocked in vitro [Sar9,Met(O2)11]substance P-induced release of acetylcholine from rat striatum. In vivo, SR140333 exerted highly potent antagonism toward [Sar9,Met(O2)11]substance P-induced hypotension in dogs (ED50 = 3 micrograms/kg i.v.), bronchoconstriction in guinea-pig (ED50 = 42 micrograms/kg i.v.) and plasma extravasation in rats (ED50 = 7 micrograms/kg i.v.). Finally, it also blocked the activation of rat thalamic neurons after nociceptive stimulation (ED50 = 0.2 micrograms/kg i.v.).

Animals↗
PubMed1993

Antitussive effect of SR 48968, a non-peptide tachykinin NK2 receptor antagonist.

The antitussive effects of SR 48968, a non-peptide tachykinin NK2 receptor antagonist, were investigated on citric acid-induced cough in the unanesthetized guinea-pig and compared with the effects of codeine. SR 48968 (0.01-0.3 mg/kg i.p.) inhibited in a dose-dependent manner the number of coughs induced by inhalation of an aqueous solution of citric acid with an ED50 of 0.1 mg/kg (0.17 mumol/kg). Under similar conditions, the codeine ED50 was 8 mg/kg (27 mumol/kg). Naloxone, an opioid receptor antagonist, abolished the effects of codeine but did not modify the effects of SR 48968. These data suggest that NK2 receptor stimulation might play an important role in the regulation of the cough reflex and that SR 48968 could be a potential antitussive agent.

Animals↗
PubMed1992

A potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor.

SR 48968 is a potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor. SR 48968 selectively inhibited neurokinin A binding to its receptor and was a competitive antagonist of neurokinin A-mediated contraction of different isolated smooth muscle preparations from various species including human. In vivo, the compound inhibited the bronchoconstriction induced by neurokinin A in guinea pigs. SR 48968 can be used to study the physiological or pathological role of neurokinin A and may be useful in the treatment of neurokinin A-dependent pathology.

Animals↗
PubMed1992

Effect of substance P and Sar9Met(O2)11-substance P on cutaneous capillary permeability in guinea pig skin.

The purpose of this study was to assess the effect of several drugs on the increase in cutaneous capillary permeability induced by intradermal injection of substance P (SP) and Sar9Met(O2)11-SP in guinea pig skin. On the one hand, the increase in cutaneous capillary permeability was partly reduced by spantide, promethazine, atropine or SR 40037, an inhibitor of the angiotensin-converting enzyme. On the other hand, norepinephrine and B3824, a B2-antagonist of bradykinin, showed an enhancing effect. Our results suggest that the effect of SP and Sar9Met(O2)11-SP in guinea pigs is partly mediated by histamine and acetylcholine, and that there is a relationship between tachykinins and bradykinin.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Effects on the isolated human bronchus of SR 48968, a potent and selective nonpeptide antagonist of the neurokinin A (NK2) receptors.

Tachykinins produce concentration-dependent contraction of the human isolated bronchus by stimulation of receptors that belong to the NK2 type. The aim of this study was to investigate the inhibitory effects of a new, potent, and selective nonpeptide antagonist of the neurokinin A (NKA) (NK2) receptors, SR 48968 [(S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl) butyl]benzamide] on human isolated airways. Our experiments were performed on human isolated bronchi obtained from patients with lung cancer. Phosphoramidon, 10(-5) M, was added to the bath to inhibit neurokinin metabolism. SR 48968 induced a parallel shift to the right of the concentration-response (C/R) curves to [Nle10]-NKA(4-10), a specific NK2 receptor agonist. The antagonism was of the competitive type, with a pA2 of 9.40 +/- 0.19 (slope = 0.95 +/- 0.08, n = 13). The (R)-enantiomer of SR 48968 was 100-fold less potent and a noncompetitive antagonist (slope = 0.56 +/- 0.11, n = 8); pA2 and slope of the racemate were 8.86 +/- 0.21 and 1.09 +/- 0.21 (n = 7), respectively. Under similar conditions, racemic CP-96,345, a nonpeptide NK1 antagonist, did not modify the C/R curves to [Nle10]-NKA(4-10) until 10(-7) M. SR 48968 did not modify C/R curves to acetylcholine, histamine, KCI, or PGF2 alpha on the human isolated bronchus. Finally, SR 48968 shifted to the right C/R curves to substance P on isolated human bronchi, whereas racemic CP-96,345 was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

[Spinal reflexes and somatosensory evoked potentials studied in the baboon in the presence of anti-arrhythmic drugs].

Intragastric administration of the anti-arrhythmic drugs CM 7857 (Sanofi) or disopyramide, as expected, significantly reduced the heart rate in normal baboons at rest. At the same time, the variability in the heart rate increased. In vitro studies by Sanofi have previously shown the anti-arrhythmic effects of these drugs, i.e., a slowing of the transmembrane currents evidenced in several categories of heart cells especially when activated. Similar ion currents are known to be involved in extracardiac sensory-motor activities. However the H-reflex in soleus underwent no systematic changes in latency or amplitude with the drugs; the non-nociceptive early and nociceptive late polysynaptic responses elicited in the tibialis anterior muscle by sural nerve stimulation demonstrated a barely perceptible increase in integrated EMG value. No change could be seen in latency or amplitude of the cortical potentials evoked by sciatic or sural stimulation which was also used for reflex responses. Overall there was no definitive evidence of change in the extra-cardiac sensory-motor responses in the normal awake monkey, after administration of relatively high doses of the cardio-active compounds.

Animals↗
PubMed1983

Pharmacological study of the antitussive and respiratory-analeptic properties of N-(2'-ethylpyrrolidino)diphenylacetamide hydrochloride (F 1459).

The antitussive and respiratory stimulant properties of N-(2'-ethylpyrrolidino)diphenylacetamide hydrochloride (F 1459) in animals are reported. In the mechanical stimulation of the trachea in guinea pigs and after intraperitoneal administration of the product, F 1459 showed a better antitussive action as compared to oxeladin, zipeprol, codeine and clobutinol. Low intraduodenal doses of F 1459 also reduced in cats the cough induced by the electrical stimulation of the superior laryngeal nerve. In anesthetized dogs whose respiratory functions had been depressed by morphine, F 1459 significantly increased the volume inspired per minute, an effect not due to any uncoupling effect on oxidative phosphorylation. F 1459 has local anesthetic and broncholytic properties that may play a role in the mechanism of its antitussive action. Contrarily to codeine, the test compound did not induce a decrease in the intestinal transit.

Anesthetics, Local↗
PubMed1979

Action of mannitol in various immunological experimental models.

The authors describe the inhibiting action of mannitol after repeated administration of low subcutaneous doses in a number of experimental immunological models. For example, in the rat it produces a reduction of the secondary arthritis of Freund's adjuvant polyarthritis and also of the pleurisy due to Bordetella pertussis hypersensitivity. In the mouse it reduces the reaction of delayed hypersensitivity to sheep red cells. Its action is also marked against ovalbumin-induced active skin anaphylaxis in the albino guinea-pig and on IgE synthesis in the rat. Moreover, after several injections it produces a reduction of carbon phagocytosis in the mouse. At the doses at which the effect appeared, no action could be found on various models of acute non-immune inflammation, diuresis, blood pressure, hematocrit and protein and plasma sodium levels.

Acute Disease↗