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Chemical Compound Review

Tocris-1635     (3aS,7aR)-2-[2-(2- methoxyphenyl)ethanimido...

Synonyms: CHEMBL131171, SureCN4349316, CHEBI:314478, LS-84754, RP-67580, ...
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Disease relevance of RP-67580


Psychiatry related information on RP-67580


High impact information on RP-67580

  • Furthermore, pretreatment with either CP, 96-345, or RP-67580 two selective NK-1 receptor antagonists inhibited poly-L-lysine-induced airway hyperresponsiveness and plasma protein extravasation [7].
  • Contractions induced by SP and septide (a selective NK1 agonist) in guinea pig ileum were competitively inhibited by RP 67580 (pA2 = 7.16 and 7.59, respectively) [1].
  • Because these studies suggested that CGRP potentiated the afferent renal nerve activity responses to substance P, we examined whether the afferent renal nerve activity response to CGRP was blocked by a substance P receptor antagonist, RP67580 [8].
  • RP67580 blocked the afferent renal nerve activity response to CGRP by 85+/-12% (P<0.02) [8].
  • The NK-1 antagonist RP 67580 also showed a higher potency for [3H]ALIE-124 than for [3H][Pro9]SP-specific binding sites [9].

Chemical compound and disease context of RP-67580


Biological context of RP-67580

  • In comparison, the affinity of RP67580, the least selective molecule, was most affected by changes at position 116, and combination with mutations at either position 97 (V-->E) or position 290 led to the human receptor phenotype [15].
  • 3. Dural vasodilatation to trigeminal stimulation was not inhibited by the calcitonin gene-related peptide-1 receptor (CGRP-1) antagonist hCGRP8-37 (15 or 50 microg kg(-1) i.v), or the neurokinin-1 receptor antagonist RP 67580 (0.1 mg kg(-1) i.v.) although both antagonists inhibited the nasal response [16].
  • Racemic RP67580 inhibited calcium entry into depolarized strips of guinea-pig ileum longitudinal muscle myenteric plexus (apparent KB = 587 +/- 115 nM), inhibited [3H]-diltiazem binding to rabbit skeletal membranes (IC50 = 298 nM) and depressed high threshold calcium currents in neurones cultured from rat cortex (10% inhibition at 10 microM) [17].
  • 4. RP67580 (10-9 mol mouse-1 i.v.) reduced the increased tracheal vascular permeability induced by a second exposure to DNS in DNFB-sensitized mice completely when injected 15 min before the second challenge (P<0.001, ANOVA) [18].
  • Antagonists to the NK1 and NK2 neurokinin receptor subtypes, RP 67580 and L-659877, respectively, were without effect, whereas the antagonist to the CGRP1 receptor, CGRP8-37, prevented the loss of vasoconstriction during repetitive nerve stimulation [19].

Anatomical context of RP-67580

  • Moreover, RP 67580 displayed the profile of a specific antagonist of NK1 receptors: it was not active on NK2 and NK3 receptors as seen in binding assays and in isolated preparations of rabbit pulmonary artery and rat portal vein [1].
  • The selective NK1 antagonist (RP 67580; 5.10(-9) mol/mouse), administered 5 min before and 1 h after the challenge, suppressed mucosal exudation and leukocyte accumulation in the airways 24 h after the challenge [20].
  • RP 67580 was a competitive inhibitor of SP responses, with an inhibition constant (KB) of 13 +/- 2 nM, in agreement with displacement studies of [3H]SP binding to membranes and intact transfected cells (Ki values of 10 +/- 4 nM, and 1.16 +/- 0.06 nM, respectively) [21].
  • 3. RP 67580 (10 nM) did not modify electrically-evoked release of calcitonin gene-related peptide-LI from rat spinal cord slices [22].
  • The non-peptide neurokinin1 receptor antagonist, RP 67580, blocks neurogenic plasma extravasation in the dura mater of rats [23].

Associations of RP-67580 with other chemical compounds


Gene context of RP-67580

  • Blockade of the NK1 receptor with RP67580, but not blockade of the CGRP receptor with CGRP(8-37), caused more severe impairment in postischemic recovery in both TRPV1(-/-) and WT hearts than in untreated hearts in both genotypes [28].
  • Tachykinin NK1 receptor blockade, by treatment with the antagonist RP67580, or absence of the tachykinin NK1 receptor resulted in a strong reduction in the accumulation of neutrophils in the bronchoalveolar lavage fluid, and in the development of tracheal hyperreactivity in mice 48 h after challenge [29].
  • The non-peptide NK1 receptor selective antagonist RP67580 inhibited responses to SPOMe, septide and/Sar9/-SP-sulphone to varying degrees with IC50 values against each of 16.0 nM (10.7-23.4 nM), 19.8 nM (8.9-37 nM) and 58.0 nM (41-89 nM), respectively [30].
  • 5. Our results indicate that RP 67580 is a selective and high affinity antagonist at central NK1 tachykinin receptors in the rat [27].
  • Neurokinin A produced increases in dural vessel diameter which were unaffected by the NK2 receptor antagonist SR 48968 but were blocked by RP67580, suggesting that neurokinin A can act through NK1 receptors to produce dural vasodilation in rats [31].

Analytical, diagnostic and therapeutic context of RP-67580


  1. Pharmacological properties of a potent and selective nonpeptide substance P antagonist. Garret, C., Carruette, A., Fardin, V., Moussaoui, S., Peyronel, J.F., Blanchard, J.C., Laduron, P.M. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  2. Protective effect of proteinase-activated receptor 2 activation on motility impairment and tissue damage induced by intestinal ischemia/reperfusion in rodents. Cattaruzza, F., Cenac, N., Barocelli, E., Impicciatore, M., Hyun, E., Vergnolle, N., Sternini, C. Am. J. Pathol. (2006) [Pubmed]
  3. Characteristics of nerve growth factor induced hyperalgesia in adult rats: dependence on enhanced bradykinin-1 receptor activity but not neurokinin-1 receptor activation. Rueff, A., Dawson, A.J., Mendell, L.M. Pain (1996) [Pubmed]
  4. Morphine, the NMDA receptor antagonist MK801 and the tachykinin NK1 receptor antagonist RP67580 attenuate the development of inflammation-induced progressive tactile hypersensitivity. Ma, Q.P., Allchorne, A.J., Woolf, C.J. Pain (1998) [Pubmed]
  5. Inhibition of emesis by tachykinin NK1 receptor antagonists in Suncus murinus (house musk shrew). Rudd, J.A., Ngan, M.P., Wai, M.K. Eur. J. Pharmacol. (1999) [Pubmed]
  6. Different behavioral profiles of the non-peptide substance P (NK1) antagonists CP-96,345 and RP 67580 in Swiss albino mice in the black-and-white box. Zernig, G., Troger, J., Saria, A. Neurosci. Lett. (1993) [Pubmed]
  7. Cationic protein-induced sensory nerve activation: role of substance P in airway hyperresponsiveness and plasma protein extravasation. Coyle, A.J., Perretti, F., Manzini, S., Irvin, C.G. J. Clin. Invest. (1994) [Pubmed]
  8. CGRP activates renal pelvic substance P receptors by retarding substance P metabolism. Gontijo, J.R., Smith, L.A., Kopp, U.C. Hypertension (1999) [Pubmed]
  9. High affinity binding of [3H]propionyl-[Met(O2)11]substance P(7-11), a tritiated septide-like peptide, in Chinese hamster ovary cells expressing human neurokinin-1 receptors and in rat submandibular glands. Sagan, S., Beaujouan, J.C., Torrens, Y., Saffroy, M., Chassaing, G., Glowinski, J., Lavielle, S. Mol. Pharmacol. (1997) [Pubmed]
  10. Involvement of neurokinin receptors in the induction but not the maintenance of mechanical allodynia in rat flexor motoneurones. Ma, Q.P., Woolf, C.J. J. Physiol. (Lond.) (1995) [Pubmed]
  11. Critical evaluation of the streptozotocin model of painful diabetic neuropathy in the rat. Fox, A., Eastwood, C., Gentry, C., Manning, D., Urban, L. Pain (1999) [Pubmed]
  12. Substance P and capsaicin-induced mechanical hyperalgesia in the rat knee joint; the involvement of bradykinin B1 and B2 receptors. Davis, A.J., Perkins, M.N. Br. J. Pharmacol. (1996) [Pubmed]
  13. Intrathecal substance P-induced thermal hyperalgesia and spinal release of prostaglandin E2 and amino acids. Hua, X.Y., Chen, P., Marsala, M., Yaksh, T.L. Neuroscience (1999) [Pubmed]
  14. Comparison of tachykinin NK1 receptors in human IM9 and U373 MG cells, using antagonist (FK888, (+/-)-CP-96,345, and RP 67580) binding. Goso, C., Potier, E., Manzini, S., Szallasi, A. Eur. J. Pharmacol. (1994) [Pubmed]
  15. Molecular determinants of the species selectivity of neurokinin type 1 receptor antagonists. Pradier, L., Habert-Ortoli, E., Emile, L., Le Guern, J., Loquet, I., Bock, M.D., Clot, J., Mercken, L., Fardin, V., Garret, C. Mol. Pharmacol. (1995) [Pubmed]
  16. Capsaicin-insensitive sensory-efferent meningeal vasodilatation evoked by electrical stimulation of trigeminal nerve fibres in the rat. Peitl, B., Pethô, G., Pórszász, R., Németh, J., Szolcsányi, J. Br. J. Pharmacol. (1999) [Pubmed]
  17. Antinociceptive activity of NK1 receptor antagonists: non-specific effects of racemic RP67580. Rupniak, N.M., Boyce, S., Williams, A.R., Cook, G., Longmore, J., Seabrook, G.R., Caeser, M., Iversen, S.D., Hill, R.G. Br. J. Pharmacol. (1993) [Pubmed]
  18. Repeated challenge with dinitrobenzene sulphonic acid in dinitrofluorobenzene-sensitized mice results in vascular hyperpermeability in the trachea: a role for tachykinins. van Houwelingen, A., van der Avoort, L.A., Heuven-Nolsen, D., Kraneveld, A.D., Nijkamp, F.P. Br. J. Pharmacol. (1999) [Pubmed]
  19. Modulation of sympathetic vasoconstriction by sensory nerves and nitric oxide in rat irideal arterioles. Hill, C.E., Gould, D.J. J. Pharmacol. Exp. Ther. (1995) [Pubmed]
  20. Mucosal exudation associated with a pulmonary delayed-type hypersensitivity reaction in the mouse. Role for the tachykinins. Buckley, T.L., Nijkamp, F.P. J. Immunol. (1994) [Pubmed]
  21. Septide: an agonist for the NK1 receptor acting at a site distinct from substance P. Pradier, L., Ménager, J., Le Guern, J., Bock, M.D., Heuillet, E., Fardin, V., Garret, C., Doble, A., Mayaux, J.F. Mol. Pharmacol. (1994) [Pubmed]
  22. Effect of the tachykinin NK1 receptor antagonists, RP 67580 and SR 140333, on electrically-evoked substance P release from rat spinal cord. Malcangio, M., Bowery, N.G. Br. J. Pharmacol. (1994) [Pubmed]
  23. The non-peptide neurokinin1 receptor antagonist, RP 67580, blocks neurogenic plasma extravasation in the dura mater of rats. Shepheard, S.L., Williamson, D.J., Hill, R.G., Hargreaves, R.J. Br. J. Pharmacol. (1993) [Pubmed]
  24. Vascular bed-dependent roles of the peptide CGRP and nitric oxide in acid-evoked hyperaemia of the rat stomach. Holzer, P., Wachter, C., Jocic, M., Heinemann, A. J. Physiol. (Lond.) (1994) [Pubmed]
  25. 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]
  26. Activation of spinal N-methyl-D-aspartate or neurokinin receptors induces long-term potentiation of spinal C-fibre-evoked potentials. Liu, X.G., Sandkühler, J. Neuroscience (1998) [Pubmed]
  27. Effects of the tachykinin NK1 receptor antagonist, RP 67580, on central cardiovascular and behavioural effects of substance P, neurokinin A and neurokinin B. Culman, J., Wiegand, B., Spitznagel, H., Klee, S., Unger, T. Br. J. Pharmacol. (1995) [Pubmed]
  28. TRPV1 gene knockout impairs postischemic recovery in isolated perfused heart in mice. Wang, L., Wang, D.H. Circulation (2005) [Pubmed]
  29. The tachykinin NK1 receptor is crucial for the development of non-atopic airway inflammation and hyperresponsiveness. van der Kleij, H.P., Kraneveld, A.D., Redegeld, F.A., Gerard, N.P., Morteau, O., Nijkamp, F.P. Eur. J. Pharmacol. (2003) [Pubmed]
  30. Receptors mediating tachykinin-evoked depolarisations of neurons in the neonatal rat spinal cord. Fox, A.J., Naeem, S., Patel, I.A., Walpole, C., Urbán, L. Acta. Biol. Hung. (1996) [Pubmed]
  31. Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural vessel diameter in the anaesthetized rat. Williamson, D.J., Hargreaves, R.J., Hill, R.G., Shepheard, S.L. Cephalalgia : an international journal of headache. (1997) [Pubmed]
  32. Renal effects of intrathecally injected tachykinins in the conscious saline-loaded rat: receptor and mechanism of action. Yuan, Y.D., Couture, R. Br. J. Pharmacol. (1997) [Pubmed]
  33. Participation of NK1 receptors in nociceptin-induced modulation of rat knee joint mechanosensitivity. McDougall, J.J., Hanesch, U., Pawlak, M., Schmidt, R.F. Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. (2001) [Pubmed]
  34. Lack of a role for substance P in the control of dural arterial flow. Carmody, J., Pawlak, M., Messlinger, K. Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. (1996) [Pubmed]
  35. Role of capsaicin-sensitive sensory nerves in mediation of the cardiovascular effects of the essential oil of croton zehntneri leaves in anaesthetized rats. Siqueira, R., Leal-Cardoso, J., Couture, R., Lahlou, S. Clin. Exp. Pharmacol. Physiol. (2006) [Pubmed]
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