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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
Chemical Compound Review

Talnetant     3-hydroxy-2-phenyl-N-(1...

Synonyms: SureCN74221, CHEMBL275544, CHEBI:106596, CID133090, DCL000241, ...
 
 
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Disease relevance of Talnetant

  • Studies with talnetant and other selective NK3 receptor antagonists are, therefore, revealing an exciting and novel pathway by which pathological changes in intestinal motility and nociception can be induced, suggesting a role for NK3 receptor antagonism in irritable bowel syndrome [1].
  • Senktide-induced miosis was inhibited by SB 222200 (1 and 2 mg kg[-1], i.v., i.e. 2.63 and 5.26 micromol kg[-1]; maximum inhibition 100%; n=3-4), SB 223412 (0.5 and 1 mg kg[-1], i.v., i.e. 1.31 and 2.61 micromol kg[-1]; maximum inhibition 100%; n=3), SB 218795 (0.5 and 1 mg kg[-1] i.v., i.e. 1.26 and 2 [2].
  • This study was designed to determine whether NK3 receptor antagonists crossing (talnetant) or not (SB-235375) the blood-brain barrier reduce the nociceptive response to colo-rectal distension (CRD) and whether NK3 antagonism reduces inflammation- or stress-induced hypersensitivity to rectal distension [3].
 

High impact information on Talnetant

  • Overall, the biological data indicate that (S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (53, SB 223412) may serve as a pharmacological tool in animal models of disease to assess the functional and pathophysiological role of the NK-3 receptor and to establish therapeutic indications for non-peptide NK-3 receptor antagonists [4].
  • SB 223412 enantioselectively inhibited the NKB-induced Ca++ mobilization in HEK 293 cells stably expressing the hNK-3 receptor [5].
  • Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist [5].
  • In mice, oral administration of SB 223412 produced dose-dependent inhibition of behavioral responses induced by the NK-3 receptor-selective agonist, senktide (ED50 = 12.2 mg/kg) [5].
  • In addition, SB 223412 antagonized senktide-induced contraction in the isolated rabbit iris sphincter muscle (Kb = 1.6 nM) [5].
 

Chemical compound and disease context of Talnetant

 

Biological context of Talnetant

  • Pharmacokinetic evaluation of SB 223412 in rat and dog indicated low plasma clearance, oral bioavailability and high and sustained plasma concentrations after 4 to 8 mg/kg oral dosages [5].
  • We have examined the effects of the NK(3) receptor antagonist, talnetant, on peristalsis in guinea-pig isolated ileum induced by optimal and by supra-maximal distension pressures [7].
 

Anatomical context of Talnetant

  • SB 223412 demonstrated enantioselective affinity for inhibition of [125I][MePhe7]neurokinin B (NKB) binding to membranes of CHO cells expressing the hNK-3 receptor (CHO hNK-3) [5].
  • 3 Peristaltic waves in the ileum elicited by optimal distension pressures (1-3 cmH(2)O) were unaffected by talnetant at a supra-maximal concentration (250 nm) [7].
 

Associations of Talnetant with other chemical compounds

 

Gene context of Talnetant

  • SB 223412 was selective for hNK-3 receptors compared with hNK-1 (>10,000-fold selective) and hNK-2 receptors (>140-fold selective), and selectivity was further demonstrated by its lack of effect, in concentrations up to 1 or 10 microM, in >60 receptor, enzyme and ion channel assays [5].
  • SB 223412 (10-1,000 nM) produced concentration-dependent rightward shifts in NKB-induced Ca++ mobilization concentration-response curves with a Kb value of 3 nM [5].
 

Analytical, diagnostic and therapeutic context of Talnetant

References

  1. Neurokinin NK1 and NK3 receptors as targets for drugs to treat gastrointestinal motility disorders and pain. Sanger, G.J. Br. J. Pharmacol. (2004) [Pubmed]
  2. In vitro and in vivo characterization of NK3 receptors in the rabbit eye by use of selective non-peptide NK3 receptor antagonists. Medhurst, A.D., Hay, D.W., Parsons, A.A., Martin, L.D., Griswold, D.E. Br. J. Pharmacol. (1997) [Pubmed]
  3. Intestinal anti-nociceptive behaviour of NK3 receptor antagonism in conscious rats: evidence to support a peripheral mechanism of action. Fioramonti, J., Gaultier, E., Toulouse, M., Sanger, G.J., Bueno, L. Neurogastroenterol. Motil. (2003) [Pubmed]
  4. Discovery of a novel class of selective non-peptide antagonists for the human neurokinin-3 receptor. 2. Identification of (S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (SB 223412). Giardina, G.A., Raveglia, L.F., Grugni, M., Sarau, H.M., Farina, C., Medhurst, A.D., Graziani, D., Schmidt, D.B., Rigolio, R., Luttmann, M., Cavagnera, S., Foley, J.J., Vecchietti, V., Hay, D.W. J. Med. Chem. (1999) [Pubmed]
  5. Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist. Sarau, H.M., Griswold, D.E., Potts, W., Foley, J.J., Schmidt, D.B., Webb, E.F., Martin, L.D., Brawner, M.E., Elshourbagy, N.A., Medhurst, A.D., Giardina, G.A., Hay, D.W. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
  6. Tachykinin receptors antagonists: from research to clinic. Quartara, L., Altamura, M. Current drug targets. (2006) [Pubmed]
  7. Modulation of peristalsis by NK(3) receptor antagonism in guinea-pig isolated ileum is revealed as intraluminal pressure is raised. Sanger, G.J., Tuladhar, B.R., Brown, J., Aziz, E., Sivakumar, D., Furness, J.B. Autonomic & autacoid pharmacology (2007) [Pubmed]
  8. In vitro and in vivo characterization of the non-peptide NK3 receptor antagonist SB-223412 (talnetant): potential therapeutic utility in the treatment of schizophrenia. Dawson, L.A., Cato, K.J., Scott, C., Watson, J.M., Wood, M.D., Foxton, R., de la Flor, R., Jones, G.A., Kew, J.N., Cluderay, J.E., Southam, E., Murkitt, G.S., Gartlon, J., Pemberton, D.J., Jones, D.N., Davies, C.H., Hagan, J. Neuropsychopharmacology (2008) [Pubmed]
  9. Lithiation of functionalized fluoroquinolines: synthesis of dihalo-2-phenylquinoline-4-carboxamides and in vitro evaluation as NK-3 receptor ligands for medical imaging studies. Bennacef, I., Tymciu, S., Dhilly, M., Mongin, F., Quéguiner, G., Lasne, M.C., Barré, L., Perrio, C. J. Org. Chem. (2004) [Pubmed]
 
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