Skip to main content
NCBI home page
Cellular and Molecular Neurobiology logoLink to Cellular and Molecular Neurobiology
. 1987 Sep;7(3):271–290. doi: 10.1007/BF00711304

Neurochemical and neuropharmacological properties of 4-Fluorotranylcypromine

Ronald T Coutts 1, Tadimeti S Rao 1, Glen B Baker 1, Ronald G Micetich 1, T W Eric Hall 1
PMCID: PMC11567413  PMID: 3440283

Abstract

  1. The 4-fluoro analogue of the monoamine oxidase-inhibiting antidepressant tranylcypromine was compared to the parent drug with regard to the following: inhibition of monoamine oxidases A and Bin vitro andex vivo; levels of both drugs in brain, liver, and blood after injection of equimolar doses; and effects on brain levels of the amines 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine.

  2. 4-Fluorotranylcypromine was found to be 10 times more potent than tranylcypromine at inhibiting monoamine oxidases A and Bin vitro in rat brain homogenates.

  3. After administration (0.1 mmol/kg, ip), 4-fluorotranylcypromine attained higher brain and liver levels and provided greater availability than did tranylcypromine after the injection of an equimolar amount.

  4. At the dose employed, theex vivo monoamine oxidases A and B inhibitory profiles in brain and liver over a 24-hr period following tranylcypromine and 4-fluorotranylcypromine treatment were not different from each other.

  5. Although the drugs had similar effects on inhibition of brain MAOex vivo, they differed from one another at several time intervals in the increases in concentrations of 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine produced in brain.

  6. In conclusion, fluorination of tranylcypromine in the 4 position of the phenyl ring produced a drug which was more potent than the parent drug at inhibiting MAOin vitro and attained higher levels in brain than did tranylcypromine itself after intraperitoneal injection of equimolar amounts of the drugs. 4-Fluorotranylcypromine increased the concentrations of trace amines, catecholamines, and 5-hydroxytryptamine in brain at most time intervals following intraperitoneal injection, and at some time intervals there were differences from tranylcypromine with regard to the amine concentrations produced.

Key words: tranylcypromine, 4-fluorotranylcypromine, monoamine oxidase, norepinephrine, dopamine, 5-hydroxytryptamine, ring hydroxylation, gas chromatography, high-pressure liquid chromatography

References

  1. Axelrod, J., and Saavedra, J. M. (1974). Octopamine, phenylethanolamine, phenylethylamine and tryptamine in the brain.Ciba Found. Symp. (New Ser.)2251–59. [Google Scholar]
  2. Azzaro, A. J. and Demarest, K. T. (1982). Inhibiting effects of type A and type B monoamine oxidase inhibitors on synaptosomal accumulation of [3H]dopamine: A reflection of antidepressant potency.Biochem. Pharmacol.312195–2197. [DOI] [PubMed] [Google Scholar]
  3. Baker, G. B., McKim, H. R., Calverley, D. G., and Dewhurst, W. G. (1978). Effects of the monoamine oxidase inhibitors tranylcypromine, phenelzine and pheniprazine on the uptake of catecholamines in slices from rat brain regions.Proc. Eur. Soc. Neurochem.1536. [Google Scholar]
  4. Baker, G. B., Hiob, L. E., and Dewhurst, W. G. (1980). Effects of monoamine oxidase inhibitors on release of dopamine and 5-hydroxytryptamine from rat striatumin vitro.Cell. Mol. Biol.26182–186. [PubMed] [Google Scholar]
  5. Baker, G. B., LeGatt, D. F., and Coutts, R. T. (1984). A comparison of the effects of acute and chronic administration of phenelzine and tranylcypromine on brain concentrations of 2-phenylethylamine,p-tyramine and tryptamine in the rat. InNeurobiology of the Trace Amines (A. A. Boulton, G. B. Baker, W. G. Dewhurst, and M. Sandler, Eds.), Humana Press, Clifton, N.J., pp. 277–282. [Google Scholar]
  6. Baker, G. B., Hampson, D. R., Coutts, R. T., Micetich, R. G., Hall, T. W., and Rao, T. S. (1986a). Detection and quantitation of a ring-hydroxylated metabolite of the antidepressant drug tranylcypromine.J. Neural Transm.65233–244. [DOI] [PubMed] [Google Scholar]
  7. Baker, G. B., Rao, T. S., and Coutts, R. T. (1986b). Electron-capture gas chromatographic analysis ofβ-phenylethylamine in tissues and body fluids using pentafluorobenzenesulfonyl chloride for derivatization.J. Chromatogr. Biomed. Appl.381211–217. [DOI] [PubMed] [Google Scholar]
  8. Baselt, R. C., Stewart, C. B., and Shaskan, E. (1977). Determination of serum and urine concentrations of tranylcypromine by electron-capture gas-liquid chromatography.J. Anal. Toxicol.1215–217. [Google Scholar]
  9. Boulton, A. A. (1976). Cerebral arylalkylaminergic mechanisms. InTrace Amines and the Brain (E. Usdin and M. Sandler, Eds.), Marcel Dekker, New York, pp. 22–39. [Google Scholar]
  10. Boulton, A. A. (1984). Trace amines and the neurosciences: An overview. InNeurobiology of Trace Amines (A. A. Boulton, G. B. Baker, W. G. Dewhurst, and M. Sandler, Eds.), Humana Press, Clifton, N.J., pp. 13–24. [Google Scholar]
  11. Boulton, A. A., Philips, S. R., and Durden, D. A. (1973). The analysis of certain amines in tissues and body fluids as their dansyl derivatives.J. Chromatogr.82137–142. [DOI] [PubMed] [Google Scholar]
  12. Calverley, D. G., Baker, G. B., Coutts, R. T., and Dewhurst, W. G. (1981). A method for the measurement of tranylcypromine in rat brain regions using gas chromatography with electron capture detection.Biochem. Pharmacol.30(8):861–867. [DOI] [PubMed] [Google Scholar]
  13. Dewhurst, W. G. (1984). Trace amines: The early years. InNeurobiology of Trace Amines (A. A. Boulton, G. B. Baker, W. G. Dewhurst, and M. Sandler, Eds.), Humana Press, Clifton, N.J., pp. 3–12. [Google Scholar]
  14. Dewhurst, W. G. (1968). New theory of cerebral amine function and its clinical application.Nature (Lond.)2181130–1133. [DOI] [PubMed] [Google Scholar]
  15. Edwards, D. J., Mallinger, A. G., Knopf, S., and Himmelhoch, J. (1985) Determination of tranylcypromine in plasma using gas chromatography-chemical-ionization mass spectrometry.J. Chromatogr. Biomed. Appl.344356–361. [DOI] [PubMed] [Google Scholar]
  16. Fenkelstein, J., Chiang, E., and Lei, J. (1965). Synthesis of cis- and trans-2-phenoxycyclopropylamines and related compounds.J. Med. Chem.8432–439. [DOI] [PubMed] [Google Scholar]
  17. Fischer, A., and Miller, I. J. (1969). Dissociation of trans-2-arylcyclopropylammonium ions and rates of 2,4-dinitrophenylation of trans-2-arylcyclopropylamines.J. Chem. Soc. B 1135-1137.
  18. Fuentes, J. A., Oleshansky, M. A., and Neff, N. H. (1976). Comparison of the antidepressant activity of (−) and (+) tranylcypromine in an animal model.Biochem. Pharmacol.25801–804. [DOI] [PubMed] [Google Scholar]
  19. Fuller, R. F., and Molloy, B. B. (1976). The effect of aliphatic fluorine on amine drugs. InBiochemistry Involving Carbon-Fluorine Bonds (R. Filler, Ed.), American Chemical Society, Washington, D.C., pp. 77–97. [Google Scholar]
  20. Gentil, V., Alevizos, B., and Lader, M. (1978). Effects of single doses of tranylcypromine on platelet MAO and amine uptake in normal subjects.Biochem. Pharmacol.271197–1201. [DOI] [PubMed] [Google Scholar]
  21. Gibaldi, M., and Perrier, D. (1982). InPharmacokinetics, 2nd ed., Marcel Dekker, New York. [Google Scholar]
  22. Green, A. R., and Kelly, P. H. (1976). Evidence for concerning the involvement of 5-hydroxytryptamine in the locomotor activity produced by amphetamine or tranylcypromine plus L-DOPA.Br. J. Pharmacol.57141–147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Green, A. R., and Youdim, M. B. H. (1975). Effects of monoamine oxidase inhibition by clorgyline, deprenil or tranylcypromine on 5-hydroxytryptamine concentrations in rat brain and hyperactivity following subsequent tryptophan administration.Br. J. Pharmacol.55415–422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hampson, D. R., Baker, G. B., and Coutts, R. T. (1986). A comparison of the neurochemical properties of the stereoisomers of tranylcypromine in the central nervous system.Cell. Mol. Biol.32593–599. [PubMed] [Google Scholar]
  25. Hampson, D. R., Baker, G. B., and Coutts, R. T. (1987). Neurochemical changes in rat brain amines after long-term inhibition of monoamine oxidase by a low dose of tranylcypromine.Biol. Psychiatry (in press). [DOI] [PubMed]
  26. Hendley, E. D., and Snyder, S. H. (1968). The relationship between the action of monoamine oxidase inhibitors on the noradrenaline uptake system and their antidepressant efficacy.Nature (Lond.)2201330–1331. [DOI] [PubMed] [Google Scholar]
  27. Himmelhoch, J. M., Fuchs, C. Z., and Symons, B. J. (1982). A double blind study of tranylcypromine treatment of major anergic depression.J. Nerv. Ment. Dis.170628–634. [DOI] [PubMed] [Google Scholar]
  28. Holman, R. B., Seagraves, E., Elliot, C. R., and Barchas, J. D. (1976). Stereotyped hyperactivity in rats treated with tranylcypromine and specific inhibitors of 5-HT uptake.Behav. Biol.16507–514. [DOI] [PubMed] [Google Scholar]
  29. Horn, A. S., and Snyder, S. H. (1972). Steric requirements for catecholamine uptake by rat brain synaptosomes, studies with rigid analogs of amphetamine.J. Pharmacol. Exp. Ther.180523–530. [PubMed] [Google Scholar]
  30. Kaiser, C., Trost, B. M., Becson, J., and Weinstock, J. (1965). Preparation of some cyclopropanes and stable sulfoxoniumylides from dimethylsulfoxonium methylide.J. Org. Chem.303972–3975. [Google Scholar]
  31. Kang, G. I., and Chung, S. Y. (1984). Mechanism of monoamine oxidase inhibition. 1. Identification of N-acetyl-and hydroxylated N-acetyltranylcypromine from tranylcypromine-dosed rat urine.Arch. Pharmacal. Res.765–68. [Google Scholar]
  32. Lang, V. A., Geissler, H. E., and Mutschler, E. (1979). Bestimmung und Vergleich der Plasma und UrineKonzentrationen nach Gabe von (+)- und (−)-Tranylcypromin.Arzeim. Forsch.29154–157. [PubMed] [Google Scholar]
  33. Mallinger, A. G., Edwards, D. J., Himmelhoch, J. M., Knopf, S., and Ehler, J. (1986). Pharmacokinetics of tranylcypromine in patients who are depressed: Relationship to cardiovascular effects.Clin. Pharmacol. Ther.40444–450. [DOI] [PubMed] [Google Scholar]
  34. McKim, H. R., Calverley, D. G., Philips, S. R., Baker, G. B., and Dewhurst, W. G. (1980). The effect of tranylcypromine on the levels of some cerebral amines in rat diencephalon. InRecent Advances in Canadian Neuropsychopharmacology (P. Grof and B. M. Saxena, Eds.), Karger, Basel, pp. 7–13. [Google Scholar]
  35. Philips, S. R. (1984). Analysis of trace amines: Endogenous levels and the effects of various drugs and tissue concentrations. InNeurobiology of the Trace Amines (A. A. Boulton, G. B. Baker, W. G. Dewhurst, and M. Sandler, Eds.), Humana Press, Clifton, N.J., pp. 127–144. [Google Scholar]
  36. Philips, S. R., and Boulton, A. A. (1979). The effects of monoamine oxidase inhibitors on some arylalkylamines in rat striatum.J. Neurochem.33159–167. [DOI] [PubMed] [Google Scholar]
  37. Philips, S. R., Baker, G. B., and McKim, H. R. (1980). Effects of tranylcypromine on the concentrations of some trace amines in the diencephalon and hippocampus of the rat.Experientia36241–242. [DOI] [PubMed] [Google Scholar]
  38. Price, L. H., Charney, D. S., and Heninger, G. R. (1985). Efficacy of lithium-tranylcypromine treatment in refractory depression.Am. J. Psychiat.142619–623. [DOI] [PubMed] [Google Scholar]
  39. Quitkin, F., Rifkin, A., and Klein, D. F. (1979). Monoamine oxidase inhibitors. A review of antidepressant effectiveness.Arch. Gen. Psychiat.36749–760. [DOI] [PubMed] [Google Scholar]
  40. Rao, T. S. (1987). Ph.D. thesis, University of Alberta, Edmonton.
  41. Rao, T. S., Baker, G. B., and Coutts, R. T. (1986a). Pentafluorobenzenesulfonyl chloride as a sensitive reagent for the rapid gas chromatographic analysis of tranylcypromine in tissues and body fluids.Biochem. Pharmacol.351925–1928. [DOI] [PubMed] [Google Scholar]
  42. Rao, T. S., Coutts, R. T., Baker, G. B., Hall, T. W., and Micetich, R. G. (1986b). Analogs of tranylcypromine: Comparison of effects on monoamine oxidasein vitro.Proc. West Pharmacol. Sci.29279–281. [Google Scholar]
  43. Reynolds, G. P., Rausch, W. G., and Riederer, P. (1980). Effects of tranylcypromine stereoisomers on monoamine oxidation in man.Br. J. Clin. Pharmacol.9521–523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Robinson, D. S., Campbell, I. C., Walker, M., Statham, N. H., Lovenberg, W., and Murphy, D. C. (1979). Effects of chronic monoamine oxidase inhibitor treatment on biogenic amine metabolism in rat brain.Neuropharmacology18771–776. [DOI] [PubMed] [Google Scholar]
  45. Rudorfer, M. V., and Potter, W. Z. (1985). Metabolism of drugs used in affective disorders. InPharmacotherapy of Affective Disorders: Theory and Practice (W. G. Dewhurst and G. B. Baker, Eds.), New York University Press, New York, pp. 382–448. [Google Scholar]
  46. Sanders-Bush, E., Bushing, J. A., and Sulser, F. (1975). Long-term effects ofp-chloroamphetamine and related drugs on central serotonergic mechanisms.J. Pharmacol. Exp. Ther.19233–41. [PubMed] [Google Scholar]
  47. Schildkraut, J. J. (1970). Tranylcypromine: Effects on norepinephrine metabolism in rat brain.Am. J. Psychiat.126925–931. [DOI] [PubMed] [Google Scholar]
  48. Silverman, R. B. (1983). Mechanism of inactivation of monoamine oxidase by trans-2-phenylcyclopropylamine and the structure of the enzyme-inactivator adduct.J. Biol. Chem.25814766–14769. [PubMed] [Google Scholar]
  49. Smith, D. F. (1980). Tranylcypromine stereoisomers, monoaminergic transmission and behavior. A review.Pharmacopsychiatry13130–136. [Google Scholar]
  50. Smith, D. F., and Petersen, H. W. (1982). Stereoselective effect of tranylcypromine enantiomers on brain serotonin.Life Sci.312449–2454. [DOI] [PubMed] [Google Scholar]
  51. Tuomisto, J., and Smith, D. F. (1986). Effects of tranylcypromine enantiomers on monoamine uptake and release and imipramine binding.J. Neural Transm.65135–145. [DOI] [PubMed] [Google Scholar]
  52. Tuomisto, J., and Walaszek, E. J. (1974). Inhibition of histamine and 5-hydroxytryptamine uptake by trans and cis-2-phenylcyclopropylamines in rabbit blood platelets.Med. Biol.52255–259. [PubMed] [Google Scholar]
  53. Weber, H., Spahn, H., Mahrke, W., and Mutschler, E. (1984). Pharmacokinetics of tranylcypromine enantiomers in healthy volunteers.J. Pharm. Pharmacol.36:50W. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. White, K., Razani, J., Cadow, B., Gelfand, R., Palmer, R., Simpson, G., and Sloane, R. B. (1984). Tranylcypromine vs. nortriptyline vs. placebo in depressed outpatients: A controlled trial.Psychopharmacology82258–262. [DOI] [PubMed] [Google Scholar]
  55. Wurtman, R. J., and Axelrod, J. (1963). A sensitive and specific assay for the estimation of monoamine oxidase.Biochem. Pharmacol.121439–1440. [DOI] [PubMed] [Google Scholar]
  56. Zirkle, C. L., Kaiser, C., Tedeschi, D. H., Tedeschi, R. E., and Burger, A. (1962). 2-Substituted cyclopropylamines. II. Effect of structure upon monoamine oxidase inhibitory activity as measuredin vivo by potentiation of tryptamine convulsions.J. Med. Chem.51265–1284. [PubMed] [Google Scholar]

Articles from Cellular and Molecular Neurobiology are provided here courtesy of Springer

RESOURCES