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Research ArticleNEUROPHARMACOLOGY

Cannabinoid Properties of Methylfluorophosphonate Analogs

Billy R. Martin, Irina Beletskaya, Gray Patrick, Reneé Jefferson, Ramona Winckler, Dale G. Deutsch, Vincenzo Di Marzo, Olivier Dasse, Ann Mahadevan and Raj K. Razdan
Journal of Pharmacology and Experimental Therapeutics September 2000, 294 (3) 1209-1218;
Billy R. Martin
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Irina Beletskaya
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Gray Patrick
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Reneé Jefferson
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Ramona Winckler
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Dale G. Deutsch
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Vincenzo Di Marzo
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Olivier Dasse
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Ann Mahadevan
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Raj K. Razdan
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Abstract

Methylarachidonylfluorophosphonate (MAFP) and related analogs have been shown to inhibit fatty acid amidohydrolase activity (FAAH), the enzyme responsible for hydrolysis of the endogenous cannabinoid ligand anandamide. To fully characterize this class of compounds, methylfluorophosphonate compounds with saturated alkyl chains ranging from C8 to C20 along with C20 unsaturated derivatives were synthesized and evaluated for their ability to interact with the CB1 receptor, inhibit FAAH, and produce in vivo pharmacological effects. These analogs demonstrated widely varying affinities for the CB1 receptor. Of the saturated compounds, C8:0 was incapable of displacing [3H]CP 55,940 binding, whereas C12:0 exhibited high affinity (2.5 nM). The C20:0 saturated analog had low affinity (900 nM), but the introduction of unsaturation into the C20 analogs restored receptor affinity. However, none of the analogs were capable of fully displacing [3H]CP 55,940 binding. On the other hand, all compounds were able to completely inhibit FAAH enzyme activity, with the C20:0 analog being the least potent. The most potent FAAH inhibitor was the short-chained saturated C12:0, whereas the other analogs were 15- to 30-fold less potent. In vivo, the C8:0 and C12:0 analogs were highly potent and fully efficacious in producing tetrahydrocannabinol (THC)-like effects, whereas the other analogs were either inactive or acted as partial agonists. None was capable of attenuating the agonist effects of THC. Conversely, the C20:0 analog potentiated the effects of anandamide but not those of 2-arachidonoyl-glycerol and THC. The high in vivo potency of the novel short-chain saturated MAFP derivatives (C8:0 and C12:0) underscores the complexity of manipulating the endogenous cannabinoid system.

Footnotes

  • Send reprint requests to: Dr. Billy R. Martin, Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Box 980613, MCV Station, Richmond, VA 23298-0613. E-mail: Martinb{at}hsc.vcu.edu

  • ↵1 This research was supported by National Institute on Drug Abuse Grant P01-DA09789. V.D.M. was the recipient of a Human Frontier in Science Program short-term fellowship.

  • Abbreviations:
    THC
    tetrahydrocannabinol
    MPE
    maximum possible effect
    MAFP
    methylarachidonylfluorophosphonate
    PMSF
    phenylmethylsulfonyl fluoride
    FAAH
    fatty acid amidohydrolase activity
    2-Ara-Gl
    2-arachidonoyl-glycerol
    CL
    confidence limits
    i.t.
    intrathecal
    DMSO
    dimethyl sulfoxide
    • Received February 11, 2000.
    • Accepted May 2, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 3
1 Sep 2000
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Research ArticleNEUROPHARMACOLOGY

Cannabinoid Properties of Methylfluorophosphonate Analogs

Billy R. Martin, Irina Beletskaya, Gray Patrick, Reneé Jefferson, Ramona Winckler, Dale G. Deutsch, Vincenzo Di Marzo, Olivier Dasse, Ann Mahadevan and Raj K. Razdan
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 1209-1218;

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Research ArticleNEUROPHARMACOLOGY

Cannabinoid Properties of Methylfluorophosphonate Analogs

Billy R. Martin, Irina Beletskaya, Gray Patrick, Reneé Jefferson, Ramona Winckler, Dale G. Deutsch, Vincenzo Di Marzo, Olivier Dasse, Ann Mahadevan and Raj K. Razdan
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 1209-1218;
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