Open Access Peer-reviewed Research Article

Main Article Content

Sujie Liu
Xin Wang
Huan Gao
Liang Ye
Jingwei Tian
Guangying Du corresponding author

Abstract

The purpose of this paper is to evaluate the pharmacodynamics of a new 5-HT2A receptor inverse agonist PCC03039 and provide data support for its druggability and clinical trial application. In the in vitro efficacy studies, the affinities of PCC03039 for 5-HT2A, 5-HT2B, and 5-HT2C receptors and the inverse agonistic and antagonistic activities of 5-HT2A receptors were detected; in the in vivo efficacy studies, the pharmacodynamic effects of PCC03039 on DOI-induced rat head-twitch model and MK-801-induced rat hyperlocomotion model were observed. The results of the studies showed that the affinities of PCC03039 for the 5-HT2 receptors were comparable to those of the marketed drug pimavanserin, however, the inverse agonistic and antagonistic activities of PCC03039 for the 5-HT2A receptor were significantly improved, with IC50 values of 2.11 nM and 1.33 nM, which were 20-fold and 21-fold higher than that of pimavanserin, respectively. PCC03039 could dose-dependently inhibit DOI-induced head-twitch and MK-801-induced hyperlocomotion in SD rats, and the pharmacodynamic effect was significantly better than pimavanserin at the equimolar dose. The above results show that PCC03039 has better pharmacodynamic activity in vitro and in vivo than pimavanserin, and has good druggability from the perspective of pharmacodynamics.

Keywords
Parkinson’s disease psychosis, 5-HT₂ᴀ receptor, inverse agonist, PCC03039

Article Details

How to Cite
Liu, S., Wang, X., Gao, H., Ye, L., Tian, J., & Du, G. (2022). Pharmacodynamics study of a new 5-HT₂ᴀ receptor inverse agonist PCC03039. Journal of Pharmaceutical and Biopharmaceutical Research, 3(2), 228-236. https://doi.org/10.25082/JPBR.2021.02.003

References

  1. Kalia LV and Lang DAE. Parkinson’s disease. Lancet, 2015, 386(9996): 896-912. https://doi.org/10.1016/S0140-6736(14)61393-3
  2. Fénelon G and Alves G. Epidemiology of psychosis in Parkinson’s disease. Journal of the Neurological Sciences, 2010, 289(1-2): 12-17. https://doi.org/10.1016/j.jns.2009.08.014
  3. Bloem BR, Okun MS and Christine K. Parkinson’s disease. Lancet, 2021, 397(10291): 2284-2303. https://doi.org/10.1016/S0140-6736(21)00218-X
  4. Meltzer HY, Mills R, Revell S, et al. Pimavanserin, a Serotonin2A Receptor Inverse Agonist, for the Treatment of Parkinson’s Disease Psychosis. Neuropsychopharmacology, 2010, 35(4): 881-892. https://doi.org/10.1038/npp.2009.176
  5. Michaud V. Cannabis Dopaminergic Effects Induce Hallucinations in a Patient with Parkinson’s Disease. Medicina, 2021, 57(10): 1107. https://doi.org/10.3390/medicina57101107
  6. Breier A, Buchanan RW, Kirkpatrick B, et al. Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. American Journal of Psychiatry, 1994, 15(1): 20-26. https://doi.org/10.1176/ajp.151.1.20
  7. Cheer SM and Wagstaff AJ. Quetiapine. Cns Drugs, 2004, 18(3): 173-199. https://doi.org/10.2165/00023210-200418030-00004
  8. Mcfarland K, Price DL and Bonhaus DW. Pimavanserin, a 5-HT2A inverse agonist, reverses psychosislike behaviors in a rodent model of Parkinson’s disease. Behavioural Pharmacology, 2011, 22(7): 681-692. https://doi.org/10.1097/FBP.0b013e32834aff98
  9. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet, 2014, 383(9916): 533-540. https://doi.org/10.1016/S0140-6736(13)62106-6
  10. Hacksell U, Burstein ES, Mcfarland K, et al. On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis. Neurochemical Research, 2014, 39(10): 2008-2017. https://doi.org/10.1007/s11064-014-1293-3
  11. Kumi KA, Zhu H and Mehta MU. Center for Drug Evaluation and Research, 2016. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/207318Orig1s000ClinPharmR.pdf
  12. Vanover KE . Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N- (1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)- dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist. Journal of Pharmacology & Experimental Therapeutics, 2006, 317(2): 910-919. https://doi.org/10.1124/jpet.105.097006
  13. Dashtipour K, Gupta F, Hauser RA, et al. Pimavanserin Treatment for Parkinson’s Disease Psychosis in Clinical Practice. Parkinson’s Disease, 2021, 2021(10): 1-10. https://doi.org/10.1155/2021/2603641
  14. Sammartino F, Marsh R, Rezai A, et al. Non-motor effects of subthalamic nucleus stimulation in Parkinson patients. Brain Imaging and Behavior, 2022, 16(1): 161-168. https://doi.org/10.1007/s11682-021-00487-8
  15. Burstein ES. Relevance of 5-HT2A Receptor Modulation of Pyramidal Cell Excitability for Dementia- Related Psychosis: Implications for Pharmacotherapy. CNS Drugs, 2021, 2021(1): 1-15. https://doi.org/10.1007/s40263-021-00836-7
  16. Dragana BK, Istvan B, Liu IY, et al. ENHANCE: Phase 3, Randomized, Double-Blind, Placebo- Controlled Study of Adjunctive Pimavanserin for Schizophrenia in Patients With an Inadequate Response to Antipsychotic Treatment. Schizophrenia Bulletin Open, 2022, 2022(1): 1-6. https://doi.org/10.1093/schizbullopen/sgac006
  17. Kwan C, Frouni I, Nuara SG, et al. Combined 5-HT2A and mGlu2 modulation for the treatment of dyskinesia and psychosis in Parkinson’s disease. Neuropharmacology, 2021, 186(10): 65-84. https://doi.org/10.1016/j.neuropharm.2021.108465
  18. Dashtipour K, Gupta F, Hauser RA, et al. Pimavanserin Treatment for Parkinson’s Disease Psychosis in Clinical Practice. Parkinson’s Disease, 2021, 2021(10): 1-10. https://doi.org/10.1155/2021/2603641
  19. Tampi RR, Tampi DJ, Young JJ, et al. Evidence for using pimavanserin for the treatment of Parkinson’s disease psychosis. World Journal of Psychiatry, 2019, 9(3): 47-54. https://doi.org/10.5498/wjp.v9.i3.47
  20. Steinberg M. Update on Pharmacological Treatment of Neuropsychiatric Symptoms of Dementia. Current Geriatrics Reports, 2021, 10(2): 51-57. https://doi.org/10.1007/s13670-021-00356-8