In vitro and in vivo pharmacology of S 16474, a novel dual tachykinin NK1 and NK2 receptor antagonist

Robineau, Pascale; Lonchampt, Michel; Kucharczyk, Nathalie; Krause, James E.; Regoli, Doménico; Fauchère, Jean‐Luc; Prost, Jean‐François; Canet, Emmanuel

doi:10.1016/0014-2999(95)00604-4

Cited by 22 publications

(7 citation statements)

References 26 publications

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“…The combination of the two antagonists fully abolish the electrical and mechanical responses. This con®rms that capsaicin releases endogenous tachykinins which interact with both the NK 1 and the NK 2 receptor populations (Bertrand et al, 1993;Charette et al, 1994;Ellis & Undem, 1994;Mitchell et al, 1995;Robineau et al, 1995). However, a preferential activation of NK 2 receptors by endogenous tachykinins released by capsaicin has been demonstrated (Ellis & Undem, 1994;Mitchell et al, 1995).…”

Section: Discussionmentioning

confidence: 90%

Effects of tachykinins and capsaicin on the mechanical and electrical activity of the guinea‐pig isolated trachea

Girard

Félétou

Advenier³

et al. 1997

British J Pharmacology

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The effects of tachykinins and capsaicin were studied by means of intracellular membrane potential and isometric tension recordings in the isolated trachea of the guinea‐pig. The basal membrane potential averaged −51 mV, and most preparations demonstrated spontaneous slow waves. Tetraethylammonium (TEA), a potassium channel blocker (8×10−3 M), depolarized the membrane potential to −44 mV and induced a rhythmic activity. In control solution, substance P (10−8–10−6 M), [Nle10]‐neurokinin A(4–10) (10−8–10−6 M) and capsaicin (10−7–10−6 M) induced concentration‐dependent depolarizations which were statistically significant at the highest concentration tested (depolarization by 10−6 M: 8, 11 and 16 mV for the NK1 agonist, the NK2 agonist and capsaicin, respectively). In the presence of TEA (8×10−3 M), the three substances induced depolarizations which were statistically significant at the highest concentration tested for substance P (10−6 M) and at 10−7 and 10−6 M for both [Nle10]‐neurokinin A(4–10) and capsaicin (depolarization by 10−6 M: 11, 17 and 10 mV for substance P, [Nle10]neurokinin A(4–10) and capsaicin, respectively). In the presence or absence of tetraethylammonium, [MePhe7]‐neurokinin B (10−8–10−6 M) did not induce any significant changes in membrane potential. The depolarizing effects of substance P (10−6 M) and [Nle10]‐neurokinin A(4–10) (10−6 M) were blocked only by the specific antagonists for NK1 and NK2 receptors, SR 140333 (10−7 M) and SR 48968 (10−7 M), respectively. The effects of capsaicin (10−6 M) were partially inhibited by each antagonist and fully blocked by their combination. Substance P (10−9 to 10−4 M), [Nle10]‐neurokinin A(4–10) (10−10 to 10−5 M), [MePhe7]‐neurokinin B and capsaicin (10−7 to 10−5 M) evoked concentration‐dependent contractions. The contractions to substance P were significantly inhibited by SR 140333 (10−8 to 10−6 M) but unaffected by SR 48968 (10−8 to 10−6 M). Furthermore, the response to [Nle10]‐neurokinin A(4–10) was significantly inhibited by SR 48968 and unaffected by SR 140333 at the same concentrations. Although SR 48968 (10−7 M) alone did not influence the effects of substance P, it potentiated the inhibitory effect of SR 140333 (10−7 M). A similar synergetic effect of these two compounds was observed in the inhibition of the contractile response to [Nle10]‐neurokinin A(4–10). Neither SR 140333 (10−7 M) nor SR 48968 (10−7 M) alone influenced the contractions to [MePhe7]‐neurokinin B and capsaicin. However, the combination of the two antagonists abolished the contractions to either peptide. These results demonstrate that the stimulation of both NK1 and NK2 tachykinin‐receptors induced contraction and depolarization of the guinea‐pig tracheal smooth muscle and that both receptors were stimulated during the endogenous release of tachykinins by capsaicin. There was no evidence for a major role of NK3 receptors in the contractile and electrical activity of the guinea‐pig isolated trachea. British Journal of Pharmacology (1997) 122, 841–848; doi:

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Section: Discussionmentioning

confidence: 90%

Effects of tachykinins and capsaicin on the mechanical and electrical activity of the guinea‐pig isolated trachea

Girard

Félétou

Advenier³

et al. 1997

British J Pharmacology

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“…CHO cells stably expressing the human ileum NK 2 receptor, CHO-hNK 2 R cells, were provided by Dr. J.E. Krause (Robineau et al 1996). Cells were cultured in minimum essential Eagle's medium α modification (α-MEM), supplemented with 10% fetal bovine serum (FBS) and geneticin 0.2 mg/ml, in a humidified atmosphere of 5% CO 2 -95% air at 37°C until slightly confluent.…”

Section: Methodsmentioning

confidence: 99%

Independent coupling of the human tachykinin NK2 receptor to phospholipases C and A2 in transfected Chinese hamster ovary cells

Catalioto

Cucchi

Renzetti

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

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The human tachykinin NK2 receptor stably expressed in Chinese hamster ovary cells (CHO-hNK2R cells) was characterized by studying the effect of neurokinin A (NKA), the preferred natural ligand, and that of other agonists and antagonists in both binding experiments and functional assays. Competition experiments using [125I]NKA showed that CHO-hNK2R cells express binding sites which have high affinity for NKA (Ki=3.4+/-0.9 nM), GR 64349 (Ki=12+/-3 nM) and [betaAla8]NKA(4-10) (Ki=21+/-8 nM) and for the antagonists MEN 10627 (Ki=0.55+/-0.2 nM), and MEN 11420 (Ki=2.4+/-0.8 nM). In contrast, the tachykinin NK1 and NK3 receptor agonists [Sar9,Met(O2)11]SP and senktide, respectively, were recognized with low affinity (Ki>10 microM). NKA (EC50=68+/-18 nM) induced a rapid and concentration-dependent increase in the intracellular level of inositoltrisphosphate (IP3). The concentration-response curve to GR 64349 (EC50=155+/-14 nM) was close to that of NKA, whereas [betaAla8]NKA(4-10) (EC50=445+/-78 nM) and SP (EC50=3197+/-669 nM) were 7- and 50-fold less potent, respectively. In addition, NKA stimulated the release of arachidonic acid and the production of prostaglandin E2 (PGE2) in a concentration-dependent manner. Also in this assay, NKA was found to be more potent than the other agonists tested (the EC50 values were 3+/-0.3, 9+/-3, 7.8+/-0.9 and 217+/-37 nM for NKA, GR 64349, [betaAla8]NKA(4-10) and SP, respectively). MEN 10627 and MEN 11420 were potent and competitive antagonists in blocking NKA-induced IP3 formation and PGE2 release: MEN 10627 and MEN 11420 displayed comparable potencies in blocking the two functional responses initiated by occupancy of the NK2 receptor by NKA. Pretreatment of the cells with pertussis toxin (500 ng/ml for 18 h) did not significantly modify the basal or stimulated phosphatidylinositol turnover but reduced the basal and NKA-induced PGE2 release by about 35%. The phospholipase C inhibitor U-73122 (10 microM) prevented the NKA-induced formation of IP3 but did not affect PGE2 release. Conversely, the phospholipase A2 inhibitor quinacrine (100 microM) blocked the release of arachidonic acid and PGE2 without affecting the NKA-stimulated formation of IP3. Chelation of extracellular calcium with 3 mM EGTA inhibited the NKA-induced PGE2 release by 81% but was without effect on basal and NKA-stimulated IP3 production. The calcium channel blockers verapamil (10 microM) and omega-conotoxin GVIA (0.1 microM) did not modify the basal PGE2 production and had no significant effect on the response to tachykinins while the blocker of non-selective cation channels, SKF-96365 (10 microM), inhibited the response to NKA by about 74%. SKF-96365 did not affect the basal or the NKA-induced IP3 formation. In conclusion, our data demonstrate that the human tachykinin NK2 receptor expressed in CHO cells displays binding affinity and functional properties which are those of a native NK2 receptor. No pharmacological evidence for heterogeneity of the human NK2 receptor was obtained in this study. Our findings indicate...

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“…These compounds can be regarded as suitable tools for the investigation of the pharmacological effect of tachykinins. Moreover, tachykinin NK 1 and NK 2 dual receptor antagonists, FK 224, S.16474 and MDL 105,212A, have been described [25][26][27]. With the development of newer and more selective ligands for the various receptors, it has become possible to clarify the respective contribution of tachykinin NK 1 , NK 2 and NK 3 activation to the pharmacological effects of tachykinins (table 2).…”

Section: Pharmacological Reviewmentioning

confidence: 99%

The role of tachykinin receptor antagonists in the prevention of bronchial hyperresponsiveness, airway inflammation and cough

Advenier¹,

Lagente²,

Boichot³

1997

Eur Respir J

113

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The excitatory nonadrenergic noncholinergic (NANC) system, involving various neuropeptides of the tachykinin family, such as substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and calcitonin gene-related peptide (CGRP), as transmitters, has now been well characterized. In airways, SP, NKA and CGRP are co-localized in the sensory unmyelinated C-fibres, which innervate all compartments of the airway wall from the trachea down to the bronchioles. C-fibre endings are found within the epithelium. They form a dense plexus in the subepithelial lamina propria, supply the glands, ramify within the smooth muscle layer and make direct contacts with postganglionic parasympathetic neurons, located in the local ganglion. In the trachea, this sensory innervation is almost exclusively derived from sensory vagal neurons, supplied by the jugular ganglion, whilst that of the lung is of mixed origin with a predominating vagal and a smaller spinal contribution [1][2][3][4][5]. The NANC system can be activated by different stimuli, which affect the chemosensitive C-fibre afferents in airways and lead to a local release of tachykinins that are responsible for several biological effects in the bronchopulmonary system: bronchospasm; increase in vascular permeability from postcapillary venules; stimulation of glandular secretion; facilitation of cholinergic neurotransmission; and recruitment and activation of some types of inflammatory cells. Sensory nerves also mediate respiratory defence reflexes, such as coughing, sneezing and secretion of mucus ( fig. 1).From these data, it has been hypothesized that abnormal stimulation of the sensory nerve terminals, e.g. induced by epithelial shedding as seen in asthma, results in enhanced release of tachykinins in the airway wall with subsequent exaggeration of inflammation. This concept of "neurogenic inflammation" introduces sensory nerve fibres as important components in the pathogenesis of asthma.The biological actions of tachykinins are mediated via three types of receptors, denoted neurokinins 1-3 (NK 1 , NK 2 and NK 3 ), which have the highest affinity for SP, NKA and NKB, respectively. This receptor classification has been established from receptor-binding and functional studies. It has now been recognized that the expression of tachykinin NK 3 receptors is confined mainly to the central and peripheral nervous system, whilst tachykinin NK 1 and tachykinin NK 2 receptors are expressed both in the central and peripheral nervous system and in target organs, including airways [5][6][7][8][9][10]. According Taken together, the results obtained with the various selective receptor antagonists provide pharmacological evidence that tachykinins play a role in delayed bronchopulmonary alterations and suggest that tachykinin receptor antagonists may be useful for investigating mechanisms and possibly reducing airway functional alterations in asthmatic patients. PHARMACOLOGICAL REVIEW

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In vitro and in vivo pharmacology of S 16474, a novel dual tachykinin NK1 and NK2 receptor antagonist

Cited by 22 publications

References 26 publications

Effects of tachykinins and capsaicin on the mechanical and electrical activity of the guinea‐pig isolated trachea

Effects of tachykinins and capsaicin on the mechanical and electrical activity of the guinea‐pig isolated trachea

Independent coupling of the human tachykinin NK2 receptor to phospholipases C and A2 in transfected Chinese hamster ovary cells

The role of tachykinin receptor antagonists in the prevention of bronchial hyperresponsiveness, airway inflammation and cough

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