PR-000608

Last updated

PR-608
PR-608.svg
Clinical data
Other namesPR 000608
Identifiers
  • 1-(4,4-Bis(4-fluorophenyl)butyl)-4-(2-hydroxy-3-phenylaminopropyl)piperazine
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C29H35F2N3
Molar mass 463.617 g·mol−1
3D model (JSmol)
  • C1CN(CCN1CCCC(C2=CC=C(C=C2)F)C3=CC=C(C=C3)F)CC(CNC4=CC=CC=C4)O
  • InChI=1S/C29H35F2N3O/c30-25-12-8-23(9-13-25)29(24-10-14-26(31)15-11-24)7-4-16-33-17-19-34(20-18-33)22-28(35)21-32-27-5-2-1-3-6-27/h1-3,5-6,8-15,28-29,32,35H,4,7,16-22H2
  • Key:YIBOKAQCZWKXIM-UHFFFAOYSA-N

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]

Contents

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.svg
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. ↑ Buzas A, Champagnac A, Dehnel A, Lavielle G, Pommier M (February 1980). "Synthesis and psychoanaleptic properties of new compounds structurally related to diphenhydramine". Journal of Medicinal Chemistry. 23 (2): 149–153. doi:10.1021/jm00176a009. PMID   6102153.
  2. ↑ "Difluanazine". PubChem. U.S. National Library of Medicine.
  3. ↑ US 3267104,Hermans HK, Karl-Adolf SW,"1,4-Disubstituted piperazines and diazepines",issued 16 August 1966, assigned to Janssen Pharmaceutica NV
  4. ↑ Hjorth S, Pettersson G (July 1993). "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. doi:10.1016/0014-2999(93)90867-H. PMID   7691622.
  5. 1 2 US 5391552,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.",issued 21 February 1995, assigned to Pola Orbis Holdings Inc.
  6. 1 2 3 Kimura M, Masuda T, Yamada K, Mitani M, Kubota N, Kawakatsu N, et al. (April 2003). "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. doi:10.1016/s0968-0896(03)00061-0. PMID   12659747.
  7. ↑ Kimura M, Masuda T, Yamada K, Mitani M, Kubota N, Kawakatsu N, et al. (September 2003). "Novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter". Bioorganic & Medicinal Chemistry. 11 (18): 3953–3963. doi:10.1016/s0968-0896(03)00428-0. PMID   12927856.
  8. ↑ Kimura M, Masuda T, Yamada K, Mitani M, Kubota N, Kawakatsu N, et al. (June 2004). "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. doi:10.1016/j.bmc.2004.02.041. PMID   15142566.
  9. ↑ Kimura M, Masuda T, Yamada K, Kubota N, Kawakatsu N, Mitani M, et al. (August 2002). "Novel diphenylalkyl piperazine derivatives with dual calcium antagonistic and antioxidative activities". Bioorganic & Medicinal Chemistry Letters. 12 (15): 1947–1950. doi:10.1016/s0960-894x(02)00322-0. PMID   12113815.
  10. ↑ Rothman RB (1990). "High affinity dopamine reuptake inhibitors as potential cocaine antagonists: a strategy for drug development". Life Sciences. 46 (20): PL17 –PL21. doi:10.1016/0024-3205(90)90466-5. PMID   2111866.
  11. ↑ Carroll FI, Howell LL, Kuhar MJ (July 1999). "Pharmacotherapies for treatment of cocaine abuse: preclinical aspects". Journal of Medicinal Chemistry. 42 (15): 2721–2736. doi:10.1021/jm9706729. PMID   10425082.
  12. ↑ Cohen BM, Carlezon WA (April 2007). "Can't get enough of that dopamine". The American Journal of Psychiatry. 164 (4): 543–546. doi:10.1176/ajp.2007.164.4.543. PMID   17403963.
  13. ↑ "PR-000608". PatSnap.
  14. ↑ Harada M, Kubota N, Masuda T, Inazu M (January 1996). "P-525: Effects of PR-000608, a novel antiparkinson drug, on MPTP-induced parkinsonism". Japanese Journal of Pharmacology. 71: 190. doi: 10.1016/S0021-5198(19)36998-7 .
  15. ↑ Brown AS, Gershon S (1993). "Dopamine and depression". Journal of Neural Transmission. General Section. 91 (2–3): 75–109. doi:10.1007/BF01245227. PMID   8099801.
  16. ↑ Orr K, Taylor D (2007). "Psychostimulants in the treatment of depression : a review of the evidence". CNS Drugs. 21 (3): 239–257. doi:10.2165/00023210-200721030-00004. PMID   17338594.
  17. ↑ Dunlop BW, Nemeroff CB (March 2007). "The role of dopamine in the pathophysiology of depression". Archives of General Psychiatry. 64 (3): 327–337. doi:10.1001/archpsyc.64.3.327. PMID   17339521.
  18. ↑ Gershon AA, Vishne T, Grunhaus L (January 2007). "Dopamine D2-like receptors and the antidepressant response". Biological Psychiatry. 61 (2): 145–153. doi:10.1016/j.biopsych.2006.05.031. PMID   16934770.
  19. ↑ Volkow ND, Wise RA, Baler R (November 2017). "The dopamine motive system: implications for drug and food addiction". Nature Reviews. Neuroscience. 18 (12): 741–752. doi:10.1038/nrn.2017.130. PMID   29142296.
  20. ↑ Volkow ND, Wise RA (May 2005). "How can drug addiction help us understand obesity?". Nature Neuroscience. 8 (5): 555–560. doi:10.1038/nn1452. PMID   15856062.
  21. ↑ da Fonseca NK, Brietzke E (August 2025). "Ultra-processed foods and dopamine: Parsing complexity beyond observed variability". Cell Metabolism. 37 (8): 1622–1623. doi:10.1016/j.cmet.2025.06.008. PMID   40769124.
  22. ↑ Heal DJ, Smith SL (June 2022). "Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology". Journal of Psychopharmacology. 36 (6): 680–703. doi:10.1177/02698811211032475. PMC   9150143 . PMID   34318734.
  23. ↑ Yu Y, Miller R, Groth SW (January 2022). "A literature review of dopamine in binge eating". Journal of Eating Disorders. 10 (1) 11. doi: 10.1186/s40337-022-00531-y . PMC   8796589 . PMID   35090565.
  24. ↑ Berner LA, Bocarsly ME, Hoebel BG, Avena NM. "Pharmacological interventions for binge eating: lessons from animal models, current treatments, and future directions". Current Pharmaceutical Design. 17 (12): 1180–1187. doi:10.2174/138161211795656774. PMID   21492094.
  25. ↑ Toth B, Burgess C, Chang K (29 May 2023). "0039 Investigating the role of striatal dopamine in sleep and narcolepsy-cataplexy". SLEEP. 46 (Supplement_1): A18. doi:10.1093/sleep/zsad077.0039.
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