Chemistry:PR-000608

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Short description: Dopamine reuptake inhibitor

PR-608
Clinical data
Other namesPR 000608
Identifiers
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC29H35F2N3
Molar mass463.617 g·mol−1
3D model (JSmol)

PR-608 is a potent dopamine reuptake inhibitor related to vanoxerine. However, the GBR class of agents was known to be derived from diphenhydramine (or more specifically flunamine) as exemplified by S-350 and bears the distinctive benzhydryl-ethyl-ether functional group.[1] PR-608 on the other hand belongs to the structurally distinct diphenylbutylpiperazine class of agents (related to the diphenylbutylpiperidine class). Other members of this class include amperozide, lidoflazine, difluanazine,[2][3] FG5865 and FG-5893.[4]

PR-608 was invented and developed in Japan and was patented in the 1990's to Pola Orbis Holdings Inc.[5]

Structure–activity relationship (SAR)

The most potent compound in the study was claimed to be 16.[6] This had a DAT IC50 of 1.75 nM. The chemical name of this compound is 1-[3-[N,N-Bis(4-fluorophenyl)amino]propyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine, PC9808585. This makes the compound virtually identical to PR-608 but has the benzhydryl carbon replaced by a tertiary nitrogen. What this means though is that it provides a site for metabolic deactivation resulting in a shorter half-life, although this remains conjectural.

Research

PR-608 has been shown in preclinical studies to inhibit dopamine uptake in the central nervous system and may have potential applications in neuropsychiatric and cardiovascular disorders.[6][7][8][5] For example, the compounds were shown to produce a marked increase in locomotor activity (LMA), without a marked decrease in blood pressure. Although PR-608 and vanoxerine showed an identical 2nM IC50 affinity for the DAT, in vivo microdialysis studies showed that PR-608 produced much more robust increases in extracellular dopamine than vanoxerine did. For example, 0.03 mmol/kg of PR-608 gave an elevation in DA of >3000% of basal values. In contrast, 0.1 mmol/kg of GBR12909 only led to ca. 1200% of basal dopamine.

The calcium channel blocking properties of PR-608 might make it useful as a cardiac stimulant for the treatment of heart disease or as a cerebral vasodilator.[9] Alternative applications of this agent include for the treatment of psychostimulant addiction,[10][11][12] neurodegenerative diseases including (but not limited to) Parkinson's disease,[13][14] and as a treatment for depression.[15][16][17][18] Since dopamine regulates the appetite,[19][20][21] PR-608 might also find use for treating binge eating disorder (BED)[22][23][24] as well as treating narcolepsy.[25]

Synthesis

PR-608 synthesis
PR-608 synthesis

The reaction of Ethyl phenylcarbamate (Phenylurethane) [101-99-5] (1) with epibromohydrin gives ethyl-N-(oxiran-2-ylmethyl)-N-phenylcarbamate, PC20325389 (2). Oxirane ring opening with 1-[4,4-bis(4-fluorophenyl)butyl]piperazine [5631-35-6] (3) occurs at the less sterically occluded end of the molecule giving Ethyl (3-{4-[4,4-bis(4-fluorophenyl)butyl]piperazin-1-yl}-2-hydroxypropyl)phenylcarbamate [143760-30-9] (4). Alkaline hydrolysis occurs to give PR-608 (5).[6]

See also

References

  1. ↑ "Synthesis and psychoanaleptic properties of new compounds structurally related to diphenhydramine". Journal of Medicinal Chemistry 23 (2): 149–153. February 1980. doi:10.1021/jm00176a009. PMID 6102153. 
  2. ↑ "Difluanazine". PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/21693. 
  3. ↑ Hermans HK, Karl-Adolf SW, "1,4-Disubstituted piperazines and diazepines", US patent 3267104, issued 16 August 1966
  4. ↑ "5-HT1A autoreceptor-mediated effects of the amperozide congeners, FG5865 and FG5893, on rat brain 5-hydroxytryptamine neurochemistry in vivo". European Journal of Pharmacology 238 (2–3): 357–367. July 1993. doi:10.1016/0014-2999(93)90867-H. PMID 7691622. 
  5. ↑ 5.0 5.1 Inazu M, Miyata Y, Morimoto T, Yamamoto T, Yoshiko Y, Harada K, Momota Y, Yanagi M, Yokota R, Katoh T, Namiki T, Kimura M, Kawakatsu N, "Diphenylpiperazine derivative and drug for circulatory organ containing the same.", US patent 5391552, issued 21 February 1995
  6. ↑ 6.0 6.1 6.2 "Syntheses of novel diphenyl piperazine derivatives and their activities as inhibitors of dopamine uptake in the central nervous system". Bioorganic & Medicinal Chemistry 11 (8): 1621–1630. April 2003. doi:10.1016/s0968-0896(03)00061-0. PMID 12659747. 
  7. ↑ "Novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter". Bioorganic & Medicinal Chemistry 11 (18): 3953–3963. September 2003. doi:10.1016/s0968-0896(03)00428-0. PMID 12927856. 
  8. ↑ "Efficient asymmetric syntheses, determination of absolute configurations and biological activities of 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine as a novel potent dopamine uptake inhibitor in the central nervous system". Bioorganic & Medicinal Chemistry 12 (11): 3069–3078. June 2004. doi:10.1016/j.bmc.2004.02.041. PMID 15142566. 
  9. ↑ "Novel diphenylalkyl piperazine derivatives with dual calcium antagonistic and antioxidative activities". Bioorganic & Medicinal Chemistry Letters 12 (15): 1947–1950. August 2002. doi:10.1016/s0960-894x(02)00322-0. PMID 12113815. 
  10. ↑ "High affinity dopamine reuptake inhibitors as potential cocaine antagonists: a strategy for drug development". Life Sciences 46 (20): PL17–PL21. 1990. doi:10.1016/0024-3205(90)90466-5. PMID 2111866. 
  11. ↑ "Pharmacotherapies for treatment of cocaine abuse: preclinical aspects". Journal of Medicinal Chemistry 42 (15): 2721–2736. July 1999. doi:10.1021/jm9706729. PMID 10425082. 
  12. ↑ "Can't get enough of that dopamine". The American Journal of Psychiatry 164 (4): 543–546. April 2007. doi:10.1176/ajp.2007.164.4.543. PMID 17403963. 
  13. ↑ "PR-000608". PatSnap. https://synapse.patsnap.com/drug/d8b30286a81649f4882c3a6f88dfb09f. 
  14. ↑ "P-525: Effects of PR-000608, a novel antiparkinson drug, on MPTP-induced parkinsonism.". Japanese Journal of Pharmacology 71: 190. January 1996. doi:10.1016/S0021-5198(19)36998-7. https://www.researchgate.net/publication/347015032. 
  15. ↑ "Dopamine and depression". Journal of Neural Transmission. General Section 91 (2–3): 75–109. 1993. doi:10.1007/BF01245227. PMID 8099801. 
  16. ↑ "Psychostimulants in the treatment of depression : a review of the evidence". CNS Drugs 21 (3): 239–257. 2007. doi:10.2165/00023210-200721030-00004. PMID 17338594. 
  17. ↑ "The role of dopamine in the pathophysiology of depression". Archives of General Psychiatry 64 (3): 327–337. March 2007. doi:10.1001/archpsyc.64.3.327. PMID 17339521. 
  18. ↑ "Dopamine D2-like receptors and the antidepressant response". Biological Psychiatry 61 (2): 145–153. January 2007. doi:10.1016/j.biopsych.2006.05.031. PMID 16934770. 
  19. ↑ "The dopamine motive system: implications for drug and food addiction". Nature Reviews. Neuroscience 18 (12): 741–752. November 2017. doi:10.1038/nrn.2017.130. PMID 29142296. 
  20. ↑ "How can drug addiction help us understand obesity?". Nature Neuroscience 8 (5): 555–560. May 2005. doi:10.1038/nn1452. PMID 15856062. 
  21. ↑ "Ultra-processed foods and dopamine: Parsing complexity beyond observed variability". Cell Metabolism 37 (8): 1622–1623. August 2025. doi:10.1016/j.cmet.2025.06.008. PMID 40769124. 
  22. ↑ "Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology". Journal of Psychopharmacology 36 (6): 680–703. June 2022. doi:10.1177/02698811211032475. PMID 34318734. 
  23. ↑ "A literature review of dopamine in binge eating". Journal of Eating Disorders 10 (1). January 2022. doi:10.1186/s40337-022-00531-y. PMID 35090565. 
  24. ↑ "Pharmacological interventions for binge eating: lessons from animal models, current treatments, and future directions". Current Pharmaceutical Design 17 (12): 1180–1187. 2011. doi:10.2174/138161211795656774. PMID 21492094. 
  25. ↑ "0039 Investigating the role of striatal dopamine in sleep and narcolepsy-cataplexy". SLEEP 46 (Supplement_1): A18. 29 May 2023. doi:10.1093/sleep/zsad077.0039. 



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