The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지

YKP1447, A Novel Potential Atypical Antipsychotic Agent

  • Published : 2009.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

(S)-Carbamic acid 2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-phenyl-ethyl ester hydrochloride (YKP1447) is a novel "atypical" antipsychotic drug which selectively binds to serotonin (5-$HT_{2A}$, Ki=0.61 nM, 5-$HT_{2C}$, Ki=20.7 nM) and dopamine ($D_2$, Ki=45.9 nM, $D_3$, Ki=42.1 nM) receptors with over $10\sim100$-fold selectivity over the various receptors which exist in the brain. In the behavioral studies using mice, YKP1447 antagonized the apomorphine-induced cage climbing ($ED_{50}$=0.93 mg/kg) and DOI-induced head twitch ($ED_{50}$=0.18 mg/kg) behavior. In the dextroamphetamine-induced hyperactivity and conditioned avoidance response (CAR) paradigm in rats, YKP1447 inhibited the hyperactivity induced by amphetamine ($ED_{50}$=0.54 mg/kg) and the avoidance response ($ED_{50}$=0.48 mg/kg); however, unlike other antipsychotic drugs, catalepsy was observed only at much higher dose ($ED_{50}$=68.6 mg/kg). Based on the CAR and catalepsy results, the therapeutic index (TI) value for YKP1447 is over 100 (i.p.). These results indicate that YKP1447 has an atypical profile and less undesirable side effects than currently available drugs.

Keywords

References

  1. Arnt J. Pharmacological specificity of conditioned avoidance response inhibition in rats. Inhibition by neuroleptics and correlation to dopamine receptor blockade. Acta Pharmacol Toxicol 51: 321−329, 1982 https://doi.org/10.1111/j.1600-0773.1982.tb01032.x
  2. Bartoszyk GD, Amsterdam C van, Böttcher H, Seyfried CA. EMD 281014, a new selective serotonin 5-HT2A receptor antagonist. Eur J Pharmacol 473: 229−230, 2003 https://doi.org/10.1016/S0014-2999(03)01992-7
  3. Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on the formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol (Kbh.) 20: 140−144, 1963
  4. Cook L, Morris RW, Mattis PA. Neuropharmacological and behavioral effects of chlorpromazine (thorazine hydrochloride). J Pharmacol Exp Ther 113: 11−12, 1955
  5. Costentin J, Protais P, Schwartz JC. Rapid and dissociated changes in sensitivities of different dopamine receptors in mouse brain. Nature 257: 405−407, 1975 https://doi.org/10.1038/257405a0
  6. Darmani NA, Martin BR, Pandey U, Glennon RA. Do functional relationships exist between 5-HT1A and 5-HT2 receptors? Pharmacol Biochem Behav 36: 901−906, 1990 https://doi.org/10.1016/0091-3057(90)90098-3
  7. Davidson AB, Weidley E. Differential effects of neuroleptic and other psychotropic agents on acquisition of avoidance in rats. Life Sci 18: 1279−1284, 1976 https://doi.org/10.1016/0024-3205(76)90205-8
  8. Dunham NW, Miya TS. A note on a simple apparatus for detecting neurological deficit in rats and mice. J Am Pharm Assoc 46: 208−209, 1957
  9. Egashira N, Mishima K, Uchida T, Hasebe N, Nagai H, Mizuki A, Iwasaki K, Ishii H, Nishimura RJ, Shoyama Y, Fujiwara M. Anandamide inhibits the DOI-induced head-twitch response in mice. Psychopharmacology 171: 382−389, 2004 https://doi.org/10.1007/s00213-003-1611-y
  10. Gustafsson B, Christensson E. Amperozide, a new putative antipsychotic drug with a limbic mode of action on dopamine mediated behavior. Pharmacol Toxicol 66 Suppl 1: 12−17, 1990 https://doi.org/10.1111/j.1600-0773.1990.tb01600.x
  11. Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28: 519−526, 2003 https://doi.org/10.1038/sj.npp.1300027
  12. Janssen PAJ, Niemegeers CJE, Smellekens KHL. Is it possible to predict the clinical effects of neuroleptic drugs (major tranquilizers) from animal data? Drug Res 15: 56−69, 1965
  13. Jones BJ, Blackburn TP. The medical benefit of 5-HT research. Pharmacol Biochem Behav 71: 555−568, 2002 https://doi.org/10.1016/S0091-3057(01)00745-6
  14. Matthysse S. Antipsychotic drug actions: a clue to the pathology of schizophrenia? Fed Proc 32: 200−205, 1973
  15. Meltzer HY, Li Z, Kaneda Y, Ichikawa J. Serotonin receptors: their key role in drugs to treat schizophrenia. Progr Neuro Psychopharmacol Biol Psychiatr 27: 1159−1172, 2003 https://doi.org/10.1016/j.pnpbp.2003.09.010
  16. Moore NA, Tye NC, Axton MS, Risius FC. The behavioral pharmacology of olanzapine, a novel "atypical" antipsychotic agent. J Pharmacol Exp Ther 262: 545−551, 1992
  17. Moore S, Kenyon P. Atypical antipsychotics, clozapine and sulpiride do not antagonize amphetamine-induced stereotyped locomotion. Psychopharmacology 114: 123−130, 1994 https://doi.org/10.1007/BF02245453
  18. Ogren SO, Hall H, Kohler C, Magnusson O, Lindbom LO, Angeby K, Florvall L. Remoxipride, a new potential antipsychotic compound with selective antidopaminergic actions in the rat brain. Eur J Pharmacol 102: 459−474, 1984 https://doi.org/10.1016/0014-2999(84)90567-3
  19. Park WK, Jeong DY, Yun CW, Lee SH, Cho HY, Kim GD, Koh HY, Pae AN, Cho YS, Choi KI, Jung JY, Jung SH, Kong JY. Pharmacological actions of a novel and selective dopamine $D_3$ receptor antagonist, KCH-1110. Pharm Research 48: 615−622, 2003 https://doi.org/10.1016/S1043-6618(03)00242-1
  20. Peroutka SJ, Snyder SH. Relationship of neuroleptic drug effects at brain dopamine, serotonin, a-adrenergic, and histamine receptors to clinical potency. Am J Psychiatry 137: 1518−1522, 1980 https://doi.org/10.1176/ajp.137.12.1518
  21. Protais P, Constentin J, Schwartz JC. Climbing behavior induced by apomorphine in mice: a simple test for the study of dopamine receptors in striatum. Psychopharmacology 50: 1−6, 1976 https://doi.org/10.1007/BF00634146
  22. Protais P, Costentin J, Schwartz JC. Climbing behavior induced by apomorphine in mice: a simple test for the study of dopamine receptors in striatum. Psychopharmacology (Berlin) 50: 1−6, 1976 https://doi.org/10.1007/BF00634146
  23. Reavill C, Kettle A, Holland V, Riley G, Blackburn TP. Attenuation of haloperidol-induced catalepsy by a $5-HT_{2C}$ receptor antagonist. Br J Pharmacol 126: 572−574, 1999 https://doi.org/10.1038/sj.bjp.0702350
  24. Schreiber R, Brocco M, Audinot V, Gobert A, Veiga S, Millan MJ. (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane)-induced head- twitches in the rat are mediated by 5-hydroxytryptamine (5-HT) 2A receptors : modulation by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists. J Pharmacol Exp Ther 273: 101−112, 1995
  25. Seeman P, Van Tol HH. Dopamine receptor pharmacology. Trends Pharmacol Sci 15: 264−270, 1994 https://doi.org/10.1016/0165-6147(94)90323-9
  26. Sibley DR, Monsma Jr FJ, Shen Y. Molecular neurobiology of dopaminergic receptors. Int Rev Neurobiol 35: 391−415, 1993 https://doi.org/10.1016/S0074-7742(08)60573-5
  27. Snyder SH, Banergee SP, Yamamura HI, Greenberg D. Drugs, neurotransmitters and schizophrenia. Science 184: 1243−1245, 1974 https://doi.org/10.1126/science.184.4143.1243
  28. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC. Molecular cloning and characterization of a novel dopamine receptor D3 as a target for neuroleptics. Nature 347: 146−151, 1990 https://doi.org/10.1038/347146a0
  29. Sokoloff P, Schwartz JC. Novel dopamine receptors half a decade later. Trends Pharmacol Sci 16: 270−275, 1995 https://doi.org/10.1016/S0165-6147(00)89044-6
  30. Stahl SM. Psychopharmacology of antidepressants. 1st ed. Martin Dunitz Ltd, London, p 31-38, 1997
  31. Van Rossum JM. The significance of dopamine-receptor blockade for the action of neuroleptic drugs. Arch Int Pharmacodyn Ther 160: 492−494, 1966
  32. Wadenberg ML, Hicks PB. The conditioned avoidance response test re-evaluated: is it a sensitive test for the detection of potentially atypical antipsychotics? Neurosci Biohav Rev 23: 851−862, 1999 https://doi.org/10.1016/S0149-7634(99)00037-8
  33. Wadenberg ML, Kapur S, Soliman A, Jones C. Dopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats. Psychopharmacology 150: 422−429, 2000 https://doi.org/10.1007/s002130000466
  34. Willins DL, Meltzer HY. Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats. J Pharmacol Exp Ther 282: 699−706, 1997
  35. Yoon BS, Park EH, Park EH, Kwon JT, Hong SB, Dong SM, Kim YH, Heo J, Ji MK, Kim YG, Kwak BS, Choi JS, Kim HT. Effects of a new antipsychotic drug (YKP1447) on impaired prepulse inhibition induced by apomorphine and phencyclidine in rats. Korean J Psychopharmacol 19: 38−45, 2008
  36. Aisa B, Tordera R, Lasheras B, Del Rio J, Ramirez MJ. Effects of maternal separation on hypothalamic-pituitary-adrenal responses, cognition and vulnerability to stress in adult female rats. Neuroscience 154: 1218−1226, 2008 https://doi.org/10.1016/j.neuroscience.2008.05.011