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Chemical Compound Review

CHEMBL16192     (7S,8S)-7-benzhydryl-N-[(2...

Synonyms: SureCN675159, SureCN675160, CHEBI:116524, AC1L2XRE, CP-96345, ...
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Disease relevance of CP 96345


Psychiatry related information on CP 96345

  • The NK-1 selective antagonist CP-96,345 (0.3 microM) had a slight stimulant influence on peristalsis, whereas the NK-2 selective antagonists MEN-10,376 (10 microM), GR-94,800 (0.3 microM) and SR-48,968 (0.1 microM) led to a small inhibition of motor activity [5].

High impact information on CP 96345

  • Recently, a non-peptide substance P antagonist (CP 96345) has been shown to be effective in animal models of pain and inflammation [6].
  • Autoradiographic ligand binding to human umbilical cord sections demonstrates the presence of SP binding sites with characteristics of the neurokinin 1 (NK-1) receptor (displacement by GTP analogues and the NK-1 specific antagonist CP-96,345) on human umbilical arterial, but not venous, endothelium [7].
  • (+/-) CP-96,345 substantially attenuated bronchoconstriction and systemic vascular leak caused by administration of Sar9,Met(O2)11-Substance P (a specific NK-1 agonist), but had no effect upon bronchoconstriction induced by selective NK-2 stimulation with Nle10-Neurokinin A[4-10] [8].
  • Anesthetized, tracheostomized, opened-chest male Hartley guinea pigs were pretreated with (+/-) CP-96,345 (3 mg/kg i.v.), SR-48,968 (300 micrograms/kg i.v.), or their respective vehicles, and Evans blue dye (30 mg/kg i.v.) to label circulating albumin [8].
  • Administration of a specific substance P-receptor antagonist (CP-96,345) reduced toxin A-induced intestinal fluid secretion and inhibited neutrophil infiltration in normal, mast cell-deficient KitW/KitW-v, and mast cell-reconstituted KitW/KitW-v mice [9].

Chemical compound and disease context of CP 96345


Biological context of CP 96345


Anatomical context of CP 96345


Associations of CP 96345 with other chemical compounds

  • Intravenous injection of WAY 100635 did not disinhibit CA(3) pyramidal neuron firing in rats given saline, CP-96,345 for 2 days, or CP-96,344 for 14 days, but produced a significant enhancement of firing in rats treated with CP-96,345 for 2 weeks [20].
  • We have investigated the effects of CP-96,345 and SR-48968, new nonpeptide (neurokinin) NK1 and NK2 receptor antagonists, respectively, against bronchoconstriction and airway microvascular leakage induced by inhaled sodium metabisulfite (MBS) in anesthetized guinea pigs [21].
  • In conscious unrestrained rats, CP 96,345 induced significant and sustained increases in mean arterial pressure of DOCA-salt rats but only small, transient, and nonsignificant rises in blood pressure of sham-treated control rats [22].
  • However, substitution of Ser290 in TM VII of the rat receptor with isoleucine present in the human receptor increased the affinity for FK 888 20-fold and that for CP 96345 6-fold, corresponding to an affinity that was only about 4-fold less than the affinity for the human NK-1 receptor [23].
  • Both (2S, 3S)-[cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicy clo [2.2.2]octane-3-amine] (CP-96,345), a non-peptidic neurokinin-1 (NK-1) receptor antagonist, and CP-96,344, its inactive 2R,3R enantiomer, inhibited spermine-induced behavioural response in a dose-dependent manner [24].

Gene context of CP 96345

  • CP-96,345 significantly down-regulated CCR5 expression in MDM at both protein and mRNA levels [3].
  • Among HIV strains tested (both prototype and primary isolates), only the R5 strains (Bal, ADA, BL-6, and CSF-6) that use the CCR5 coreceptor for entry into MDM were significantly inhibited by CP-96,345; in contrast, the X4 strain (UG024), which uses CXCR4 as its coreceptor, was not inhibited [3].
  • The highly specific SP receptor antagonist, CP-96,345, completely inhibited the effect of SP but not SOM on IgG2a release [25].
  • Moreover, animals treated in vivo with the NK-1 receptor antagonist CP-96,345 produced smaller granulomas [26].
  • 4. The NK1 receptor selective agonist, [Sar9]SP sulphone (10 nM) evoked a maximal facilitatory action on cholinergic responses of 334.9 +/- 63% (P < 0.01) (pD2 = 8.5 +/- 0.06) an effect which was blocked by the selective NK1-receptor antagonist, CP 96,345 (100 nM) (P < 0.05) but not by the NK2 receptor antagonist, MEN 10,376 (100 nM) [27].

Analytical, diagnostic and therapeutic context of CP 96345


  1. Different binding epitopes on the NK1 receptor for substance P and non-peptide antagonist. Gether, U., Johansen, T.E., Snider, R.M., Lowe, J.A., Nakanishi, S., Schwartz, T.W. Nature (1993) [Pubmed]
  2. Selective inhibition of the carotid body sensory response to hypoxia by the substance P receptor antagonist CP-96,345. Prabhakar, N.R., Cao, H., Lowe, J.A., Snider, R.M. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  3. Substance P antagonist (CP-96,345) inhibits HIV-1 replication in human mononuclear phagocytes. Lai, J.P., Ho, W.Z., Zhan, G.X., Yi, Y., Collman, R.G., Douglas, S.D. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  4. CP-96,345, a substance P antagonist, inhibits rat intestinal responses to Clostridium difficile toxin A but not cholera toxin. Pothoulakis, C., Castagliuolo, I., LaMont, J.T., Jaffer, A., O'Keane, J.C., Snider, R.M., Leeman, S.E. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  5. Synergistic role of muscarinic acetylcholine and tachykinin NK-2 receptors in intestinal peristalsis. Holzer, P., Maggi, C.A. Naunyn Schmiedebergs Arch. Pharmacol. (1994) [Pubmed]
  6. Amino-aromatic interaction between histidine 197 of the neurokinin-1 receptor and CP 96345. Fong, T.M., Cascieri, M.A., Yu, H., Bansal, A., Swain, C., Strader, C.D. Nature (1993) [Pubmed]
  7. Functional neurokinin 1 receptors for substance P are expressed by human vascular endothelium. Greeno, E.W., Mantyh, P., Vercellotti, G.M., Moldow, C.F. J. Exp. Med. (1993) [Pubmed]
  8. Tachykinin receptor antagonists inhibit hyperpnea-induced bronchoconstriction in guinea pigs. Solway, J., Kao, B.M., Jordan, J.E., Gitter, B., Rodger, I.W., Howbert, J.J., Alger, L.E., Necheles, J., Leff, A.R., Garland, A. J. Clin. Invest. (1993) [Pubmed]
  9. Direct evidence of mast cell involvement in Clostridium difficile toxin A-induced enteritis in mice. Wershil, B.K., Castagliuolo, I., Pothoulakis, C. Gastroenterology (1998) [Pubmed]
  10. Role of neurogenic inflammation in antigen-induced vascular extravasation in guinea pig trachea. Bertrand, C., Geppetti, P., Baker, J., Yamawaki, I., Nadel, J.A. J. Immunol. (1993) [Pubmed]
  11. An isobolographic analysis of the effects of N-methyl-D-aspartate and NK1 tachykinin receptor antagonists on inflammatory hyperalgesia in the rat. Ren, K., Iadarola, M.J., Dubner, R. Br. J. Pharmacol. (1996) [Pubmed]
  12. Effect of bradykinin and tachykinin receptor antagonist on xylene-induced cystitis in rats. Giuliani, S., Santicioli, P., Lippe, I.T., Lecci, A., Maggi, C.A. J. Urol. (1993) [Pubmed]
  13. Comparison of antagonistic effects of sendide and CP-96,345 on a spinally mediated behavioural response in mice. Sakurada, T., Manome, Y., Katsumata, K., Tan-No, K., Sakurada, S., Ohba, M., Kisara, K. Eur. J. Pharmacol. (1994) [Pubmed]
  14. Effect of CP-96,345, a nonpeptide substance P receptor antagonist, on salivation in rats. Snider, R.M., Longo, K.P., Drozda, S.E., Lowe, J.A., Leeman, S.E. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  15. Role of substance P in blood pressure regulation in salt-dependent experimental hypertension. Kohlmann, O., Cesaretti, M.L., Ginoza, M., Tavares, A., Zanella, M.T., Ribeiro, A.B., Ramos, O.L., Leeman, S.E., Gavras, I., Gavras, H. Hypertension (1997) [Pubmed]
  16. Multiple mechanisms of arachidonic acid release in Chinese hamster ovary cells transfected with cDNA of substance P receptor. Garcia, M., Sakamoto, K., Shigekawa, M., Nakanishi, S., Ito, S. Biochem. Pharmacol. (1994) [Pubmed]
  17. A non-peptide substance P antagonist down-regulates SP mRNA expression in human mononuclear phagocytes. Lai, J.P., Ho, W.Z., Yang, J.H., Wang, X., Song, L., Douglas, S.D. J. Neuroimmunol. (2002) [Pubmed]
  18. Non-peptide antagonists, CP-96,345 and RP 67580, distinguish species variants in tachykinin NK1 receptors. Barr, A.J., Watson, S.P. Br. J. Pharmacol. (1993) [Pubmed]
  19. Injury-induced plasticity of spinal reflex activity: NK1 neurokinin receptor activation and enhanced A- and C-fiber mediated responses in the rat spinal cord in vitro. Thompson, S.W., Dray, A., Urban, L. J. Neurosci. (1994) [Pubmed]
  20. Sustained blockade of neurokinin-1 receptors enhances serotonin neurotransmission. Haddjeri, N., Blier, P. Biol. Psychiatry (2001) [Pubmed]
  21. Involvement of tachykinin receptors (NK1 and NK2) in sodium metabisulfite-induced airway effects. Sakamoto, T., Tsukagoshi, H., Barnes, P.J., Chung, K.F. Am. J. Respir. Crit. Care Med. (1994) [Pubmed]
  22. Cardiovascular effects of a specific nonpeptide antagonist of substance P (NK-1) receptor in DOCA-salt hypertension. Kohlmann, O., Ginoza, M., Cezaretti, M.L., Zanella, M.T., Ribeiro, A.B., Tavares, A., Ramos, O.L., Leeman, S.E., Gavras, I., Gavras, H. Hypertension (1995) [Pubmed]
  23. The species selectivity of chemically distinct tachykinin nonpeptide antagonists is dependent on common divergent residues of the rat and human neurokinin-1 receptors. Jensen, C.J., Gerard, N.P., Schwartz, T.W., Gether, U. Mol. Pharmacol. (1994) [Pubmed]
  24. Intrathecally administered spermine produces the scratching, biting and licking behaviour in mice. Tan-No, K., Taira, A., Wako, K., Niijima, F., Nakagawasai, O., Tadano, T., Sakurada, C., Sakurada, T., Kisara, K. Pain (2000) [Pubmed]
  25. Substance P and somatostatin can modulate the amount of IgG2a secreted in response to schistosome egg antigens in murine schistosomiasis mansoni. Blum, A.M., Metwali, A., Mathew, R.C., Elliott, D., Weinstock, J.V. J. Immunol. (1993) [Pubmed]
  26. Substance P modulates antigen-induced, IFN-gamma production in murine Schistosomiasis mansoni. Blum, A.M., Metwali, A., Cook, G., Mathew, R.C., Elliott, D., Weinstock, J.V. J. Immunol. (1993) [Pubmed]
  27. Facilitatory effects of selective agonists for tachykinin receptors on cholinergic neurotransmission: evidence for species differences. Belvisi, M.G., Patacchini, R., Barnes, P.J., Maggi, C.A. Br. J. Pharmacol. (1994) [Pubmed]
  28. Characterization of guinea pig pulmonary neurokinin type 1 receptors using a novel antagonist ligand, [3H]FK888. Miyayasu, K., Mak, J.C., Nishikawa, M., Barnes, P.J. Mol. Pharmacol. (1993) [Pubmed]
  29. Nonadrenergic, noncholinergic contractile responses of the guinea pig hilar bronchus involve the preferential activation of tachykinin neurokinin2 receptors. Renzetti, L.M., Shenvi, A., Buckner, C.K. J. Pharmacol. Exp. Ther. (1992) [Pubmed]
  30. Effects of FK224, a novel cyclopeptide NK1 and NK2 antagonist, and CP-96,345, a nonpeptide NK1 antagonist, on development and maintenance of thermal hyperesthesia evoked by carrageenan injection in the rat paw. Yamamoto, T., Shimoyama, N., Mizuguchi, T. Anesthesiology (1993) [Pubmed]
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