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NK3 receptor antagonists: the next generation of antipsychotics?

Abstract

Although current antipsychotic drugs are effective at treating the psychotic (positive) symptoms of schizophrenia, they have one or more serious side effects, including extrapyramidal symptoms, weight gain, cardiovascular liabilities and type II diabetes. However, recent data from clinical trials of selective neurokinin 3 (NK3) receptor antagonists in schizophrenia ? osanetant and talnetant ? have shown significant improvement in positive symptoms, with no major side-effects reported as yet. Here we discuss the preclinical and clinical evidence that indicates that NK3 receptor antagonists might represent a new approach to the treatment of schizophrenia and possibly other neuropsychiatric disorders.

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Figure 1: Tachykinin genes and peptides.
Figure 2: Neurokinin 3 receptor characteristics and expression.
Figure 3: Neurokinin 3 receptors and dopamine.
Figure 4: Effector systems of NK3 receptors.

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References

  1. Tamminga, C. A. & Holcomb, H. H. Phenotype of schizophrenia: a review and formulation. Mol. Psychiatry 10, 27?39 (2004).

    Article  Google Scholar 

  2. Brewer, W. J. et al. Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. Am. J. Psychiatry 162, 71?78 (2005).

    Article  Google Scholar 

  3. Schotte, A. et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl.) 124, 57?73 (1996).

    Article  CAS  Google Scholar 

  4. Meltzer, H. Y. & Stahl, S. M. The dopamine hypothesis of schizophrenia: a review. Schizophr. Bull. 2, 19?76 (1976).

    Article  CAS  Google Scholar 

  5. Leucht, S., Wahlbeck, K., Hamann, J. & Kissling, W. New generation antipsychotics versus low-potency conventional anti-psychotics: a systematic review and meta-analysis. Lancet 361, 1581?1589 (2003).

    Article  CAS  Google Scholar 

  6. Meltzer, H. Y., Matsubara, S. & Lee, J. C. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J. Pharmacol. Exp. Ther. 251, 238?246 (1989).

    CAS  PubMed  Google Scholar 

  7. Weiner, D. M. et al. 5-Hydroxytryptamine2A receptor inverse agonists as antipsychotics. J. Pharmacol. Exp. Ther. 299, 268?276 (2001).

    CAS  PubMed  Google Scholar 

  8. Meltzer, H. Y., Li, Z., Kaneda, A. & Ichikawa, J. Serotonin receptors: their role in drugs to treat schizophrenia. Progr. Neuropsychopharmacol. Biol. Psychiatry 27, 1159?1172 (2003).

    Article  CAS  Google Scholar 

  9. Albert, J. S. Neurokinin antagonists and their potential role in treating depression and other stress disorders. Expert Opin. Ther. Patents 14, 1421?1433 (2004).

    Article  CAS  Google Scholar 

  10. Emonds-Alt, X. et al. SR142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor. Life Sci. 56, PL27?PL32 (1995).

    CAS  PubMed  Google Scholar 

  11. Sarau, H. M. et al. Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB223412, a novel, potent and selective neurokinin-3 receptor antagonist. J. Pharmacol. Exp. Ther. 281, 1303?1311 (1997).

    CAS  PubMed  Google Scholar 

  12. Almeida, T. A. et al. Tachykinins and tachykinin receptors: structure and activity relationships. Curr. Med. Chem. 11, 2045?2081 (2004).

    Article  CAS  Google Scholar 

  13. Nawa, H., Kotani, H. & Nakanishi, S. Tissue specific generation of two preprotachykinin mRNAs from one gene by alternative splicing. Nature 312, 729?734 (1984).

    Article  CAS  Google Scholar 

  14. Nakanishi, S. Substance P precursor and kininogen: their structures, gene organizations and regulation. Physiol. Rev. 67, 1117?1142 (1987).

    Article  CAS  Google Scholar 

  15. Kotani, H., Hoshimaru, M., Nawa, H. & Nakanishi, S. Structure and gene organization of bovine neuromedin K precursor. Proc. Natl Acad. Sci. USA 83, 7074?7078 (1986).

    Article  CAS  Google Scholar 

  16. Nakanishi, S. Mammalian tachykinin receptors. Annu. Rev. Neurosci. 14, 123?136 (1991).

    Article  CAS  Google Scholar 

  17. Maggi, C. A. The troubled story of tachykinins and neurokinins. Trends Pharmacol. Sci. 21, 173?175 (2000).

    Article  CAS  Google Scholar 

  18. Mussap, C. J., Geraghty, D. P. & Burcher, E. Tachykinin receptors: a radioligand binding perspective. J. Neurochem. 60, 1987?2009 (1993).

    Article  CAS  Google Scholar 

  19. Seabrook, G. R., Bowery, A. J. & Hill, R. G. Pharmacology of tachykinin receptors on neurons in the ventral tegmental area of rat brain slices. Eur. J. Pharm. 273, 113?119 (1995).

    Article  CAS  Google Scholar 

  20. Wormser, U. et al. Highly selective agonists for substance P receptor subtypes. EMBO J. 5, 2805?2808 (1986).

    Article  CAS  Google Scholar 

  21. Wu, L. -H., Vartanian, A., Oxender, D. L. & Chung, F. -Z. Identification of methionine134 and alanine146 in the second transmembrane segment of the human tachykinin NK receptor as residues involved in species selective binding to SR48968. Biochem. Biophys. Res. Commun. 198, 961?966 (1994).

    Article  CAS  Google Scholar 

  22. Shughrue, P. J., Lane, M. V. & Merchenthaler, I. In situ hybridization analysis of the distribution of neurokinin-3 mRNA in the rat central nervous system. J. Comp. Neurol. 372, 395?414 (1996).

    Article  CAS  Google Scholar 

  23. Langlois, X., Wintmolders, C., Te Riele, P., Leysen, J. E. & Jurzak, M. Detailed distribution of neurokinin 3 receptors in the rat, guinea pig and gerbil brain: a comparative autoradio- graphic study. Neuropharmacology 40, 242?253 (2001).

    Article  CAS  Google Scholar 

  24. Stoessl, A. J. Localization of striatal and nigral tachykinin receptors in the rat. Brain Res. 646, 13?18 (1994).

    Article  CAS  Google Scholar 

  25. Harrison, P. J. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 122, 593?624 (1999).

    Article  Google Scholar 

  26. Stinus, L., Kelley, A. E. & Iversen, S. D. Increased spontaneous activity following substance P infusion into A10 dopaminergic area. Nature 276, 616?618 (1978).

    Article  CAS  Google Scholar 

  27. Waldmeier, P. C., Kam, R. & Stocklin, K. Increased dopamine metabolism in rat striatum after infusion of substance P into the substantia nigra. Brain Res. 159, 223?227 (1978).

    Article  CAS  Google Scholar 

  28. Humpel, C., Saria, A. & Regoli, D. Injection of tachykinins and selective neurokinin receptor ligands into the substantia nigra reticulate increases striatal dopamine and 5-hydroxytryptamine metabolism. Eur. J. Pharm. 195, 107?114 (1991).

    Article  CAS  Google Scholar 

  29. Keegan, K. D., Woodruff, G. N. & Pinnock, R. D. The selective NK3 receptor agonist senktide excites a subpopulation of dopamine-sensitive neurons in the rat substantia nigra pars compacta in vitro . Br. J. Pharmacol. 105, 3?5 (1992).

    Article  CAS  Google Scholar 

  30. Nalivaiko, E., Michaud, J. -C., Soubrie, P., Le Fur, G. & Feltz, P. Tachykinin neurokinin-1 and neurokinin-3 receptor-mediated responses in guinea-pig substantia nigra: an in vitro electrophysiological study. Neuroscience 78, 745?757 (1997).

    Article  CAS  Google Scholar 

  31. Alonso, R. et al. Evidence for modulation of dopamine-neuronal function by tachykinin NK3 receptor stimulation in gerbil mesencephalon cell cultures. Eur. J. Neurosci. 8, 801?808 (1996).

    Article  CAS  Google Scholar 

  32. Marco, N. et al. Activation of dopaminergic and cholinergic neurotransmission by tachykinin NK3 receptor stimulation: an in vivo microdialysis approach in guinea pig. Neuropeptides 32, 481?488 (1998).

    Article  CAS  Google Scholar 

  33. Stoessl, A. J., Szczutkowski, E., Glenn, B. & Watson, I. Behavioural effects of selective tachykinin agonists in midbrain dopamine regions. Brain Res. 565, 254?262 (1991).

    Article  CAS  Google Scholar 

  34. Stoessl, A. J. et al. Senktide, a selective neurokinin B-like agonist, elicits serotonin-mediated behaviour following intracisternal administration in the mouse. Neurosci. Lett. 80, 321?326 (1987).

    Article  CAS  Google Scholar 

  35. Stoessl, A. J., Dourish, C. T. & Iversen, S. D. The NK-3 tachykinin receptor agonist senktide elicits 5-HT-mediated behaviour following central or peripheral administration in mice and rats. Br. J. Pharm. 94, 285?287 (1988).

    Article  CAS  Google Scholar 

  36. Liu, R., Ding, Y. & Aghajanian, G. K. Neurokinins activate local glutamatergic inputs to serotonergic neurons of the dorsal raphe nucleus. Neuropsychopharmacology 27, 329?340 (2002).

    Article  CAS  Google Scholar 

  37. Frankland, P. W. & Bontempi, B. The organization of recent and remote memories. Nature Rev. Neurosci. 6, 119?130 (2005).

    Article  CAS  Google Scholar 

  38. Sumiyoshi, T. et al. The effect of tandospirone, a serotonin1A agonist, on memory function in schizophrenia. Biol. Psychiatry 49, 861?868 (2001).

    Article  CAS  Google Scholar 

  39. Bert, L. et al. Permissive role of neurokinin NK3 receptors in NK1 receptor-mediated activation of the locus coeruleus revealed by SR142801. Synapse 43, 62?69 (2002).

    Article  CAS  Google Scholar 

  40. Meltzer, H. Y., Arvanitis, L., Bauer, D. & Rein, W. A placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am. J. Psychiatry 161, 1?6 (2004).

    Article  Google Scholar 

  41. Kay, S. R., Fiszbein, A. & Opler, L. A. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261?276 (1987).

    Article  CAS  Google Scholar 

  42. Overall, J. E. & Gorham, D. R. The brief psychiatric rating scale. Psychol. Reports 10, 799?812 (1962).

    Article  Google Scholar 

  43. ECDEU Assessment Manual for Psychopharmacology: Publication ADM 76?338 (ed. Guy, W.) 219?222 (US Department of Health, Education, and Welfare, Washington DC, 1976).

  44. Meltzer, H. Y. & McGurk, S. R. The effect of clozapine, risperidone and olanzapine on cognitive function in schizophrenia. Schizophr. Bull. 25, 233?255 (1999).

    Article  CAS  Google Scholar 

  45. Dixon, L. et al. Variables associated with disparities in treatment of patients with schizophrenia and comorbid mood and anxiety disorders. Psychiatr. Serv. 52, 1216?1222 (2001).

    Article  CAS  Google Scholar 

  46. Cosoff, S. J. & Hafner, R. J. The prevalence of comorbid anxiety in schizophrenia, schizoaffective and bipolar disorder. Aust. N. Z. J. Psychiatry 32, 6?72 (1998).

    Article  Google Scholar 

  47. Kahn, J. P., Puertollano, M. A., Schane, M. D. & Klein, D. F. Adjunctive alprazolam for schizophrenia with panic anxiety: clinical observation and pathogenetic implications. Am. J. Psychiatry 145, 742?744 (1998).

    Google Scholar 

  48. Kronenberg, G. et al. Randomized, double-blind study of SR142801 (Osanetant). A novel neurokinin-3 (NK3) receptor antagonist in panic disorder with pre- and posttreatment cholecystokinin tetrapeptide (CCK-4) challenges. Pharmacopsychiatry 38, 24?29 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors gratefully thank T. Ballard-Yardy, P. David-Pierson, M.-C. Hernandez, T. Hoffmann, F. Knoflach, S. Nick, S. Poli, R. Porter, M. Schmitt, P. Schnider, L. Steward, A. Sleight, H. Stadler and J. Wettstein for discussions, ideas, commitments and support. We thank P. Shugrue for providing Fig 2Bb and X. Langlois for providing Fig 2Bc.

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Correspondence to Will Spooren.

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Competing interests

W.S. and C.R. are employees of F. Hoffmann-La Roche, which is developing drugs that target neurokinin receptors. H.M. is a consultant to Acadia, AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Pfizer, Solvay and Wyeth.

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DATABASES

Entrez Gene

D 2 receptor

5-HT 1A receptor

5-HT 2A receptor

5-HT 2C receptor

5-HT 6 receptor

5?HT 7 receptor

NK 1 receptor

NK 2 receptor

NK 3 receptor

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Spooren, W., Riemer, C. & Meltzer, H. NK3 receptor antagonists: the next generation of antipsychotics?. Nat Rev Drug Discov 4, 967–975 (2005). https://doi.org/10.1038/nrd1905

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