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Arzneimittelforschung 2012; 62(11): 513-518
DOI: 10.1055/s-0032-1323662
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

The Inhibition of Monoamine Oxidase by 8-(2-Phenoxyethoxy)Caffeine Analogues

B. Strydom
1   Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa
,
J. J. Bergh
1   Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa
,
J. P. Petzer
1   Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa
› Author Affiliations
Further Information

Publication History

received 11 May 2012

accepted 24 July 2012

Publication Date:
31 August 2012 (online)

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Abstract

Previous studies have documented that substituted 8-oxycaffeines act as inhibitors of human monoamine oxidase (MAO) B. A particularly potent inhibitor among the reported compounds was 8-(2-phenoxyethoxy)caffeine with an IC50 value of 0.383 µM towards MAO-B. In an attempt to improve on the inhibition potency of this compound and to discover highly potent reversible MAO-B inhibitors, in the present study, a series of 8-(2-phenoxyethoxy)caffeine analogues containing various substituents on C4 of the phenoxy ring, were synthesized and evaluated as inhibitors of human MAO-A and -B. The results show that the 8-(2-phenoxyethoxy)caffeine analogues are selective and reversible MAO-B inhibitors with the most potent homologue, 8-{2-[4-(trifluoromethyl)phenoxy]ethoxy}caffeine, exhibiting an IC50 value of 0.061 μM. These highly potent inhibitors are useful leads in the design of therapies for neurodegenerative disorders such as Parkinson’s disease.

Key words

monoamine oxidase - caffeine - 8-(2-phenoxyethoxy)caffeine - reversible inhibition - selective inhibition - structure-activity relationship
 

  • References

  • 1 Youdim MBH, Bakhle YS. Monoamine oxidase: isoforms and inhibitors in Parkinson’s disease and depressive illness. Br J Pharmacol 2006; 147: S287-S296
    PubMedSearch in Google Scholar
  • 2 Shih JC, Chen K, Ridd MJ. Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 1999; 22: 197-217
    CrossrefPubMedSearch in Google Scholar
  • 3 Youdim MBH, Edmondson DE, Tipton KF. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 2006; 7: 295-309
    CrossrefPubMedSearch in Google Scholar
  • 4 Youdim MBH, Weinstock M. Therapeutic applications of selective and non-selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation. Neurotoxicology 2004; 25: 243-250
    CrossrefPubMedSearch in Google Scholar
  • 5 Bonnet U. Moclobemide: therapeutic use and clinical studies. CNS Drug Rev 2003; 9: 97-140
    CrossrefPubMedSearch in Google Scholar
  • 6 Fernandez HH, Chen JJ. Monoamine oxidase-B inhibition in the treatment of Parkinson’s disease. Pharmacotherapy 2007; 27: 174S-185S
    CrossrefPubMedSearch in Google Scholar
  • 7 Riederer P, Youdim MBH. Monoamine oxidase activity and monoamine metabolism in brains of parkinsonian patients treated with l-deprenyl. J Neurochem 1986; 46: 1359-1365
    CrossrefPubMedSearch in Google Scholar
  • 8 Finberg JP, Wang J, Bankiewich K et al. Increased striatal dopamine production from L-DOPA following selective inhibition of monoamine oxidase B by R(+)-N-propargyl-1-aminoindan (rasagiline) in the monkey. J Neural Transm Suppl 1998; 52: 279-285
    PubMedSearch in Google Scholar
  • 9 Di Monte DA, DeLanney LE, Irwin I et al. Monoamine oxidase-dependent metabolism of dopamine in the striatum and substantia nigra of L-DOPA-treated monkeys. Brain Res 1996; 738: 53-59
    CrossrefPubMedSearch in Google Scholar
  • 10 Rabey JM, Sagi I, Huberman M et al. Rasagiline mesylate, a new MAO-B inhibitor for the treatment of Parkinson’s disease: a double-blind study as adjunctive therapy to levodopa. Clin Neuropharmacol 2000; 23: 324-330
    CrossrefPubMedSearch in Google Scholar
  • 11 Tipton KF, Boyce S, O’Sullivan J et al. Monoamine oxidases: Certainties and uncertainties. Curr Med Chem 2004; 11: 1965-1982
    CrossrefPubMedSearch in Google Scholar
  • 12 Fowler JS, Volkow ND, Logan J et al. Slow recovery of human brain MAO B after L-deprenyl (selegeline) withdrawal. Synaps 1994; 18: 86-93
    PubMedSearch in Google Scholar
  • 13 Strydom B, Malan SF, Castagnoli N et al. Inhibition of monoamine oxidase by 8-benzyloxycaffeine analogues. Bioorg Med Chem 2010; 18: 1018-1028
    CrossrefPubMedSearch in Google Scholar
  • 14 Strydom B, Bergh JJ, Petzer JP. 8-Aryl- and alkyloxycaffeine analogues as inhibitors of monoamine oxidase. Eur J Med Chem 2011; 46: 3474-3485
    CrossrefPubMedSearch in Google Scholar
  • 15 Booysen HP, Moraal C, Terre’Blanche G et al. Thio- and aminocaffeine analogues as inhibitors of human monoamine oxidase. Bioorg Med Chem 2011; 19: 7507-7518
    CrossrefPubMedSearch in Google Scholar
  • 16 Pretorius J, Malan SF, Castagnoli N et al. Dual inhibition of monoamine oxidase B and antagonism of the adenosine A2A receptor by (E,E)-8-(4-phenylbutadien-1-yl)caffeine analogues. Bioorg Med Chem 2008; 16: 8676-8684
    CrossrefPubMedSearch in Google Scholar
  • 17 Vlok N, Malan SF, Castagnoli N et al. Inhibition of monoamine oxidase B by analogues of the adenosine A2A receptor antagonist (E)-8-(3-chlorostyryl)caffeine (CSC). Bioorg Med Chem 2006; 14: 3512-3521
    CrossrefPubMedSearch in Google Scholar
  • 18 Chen JF, Steyn S, Staal R et al. 8-(3-Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism. J Biol Chem 2002; 277: 36040-36044
    CrossrefPubMedSearch in Google Scholar
  • 19 Fischer E, Reese L. Ueber caffeïn, xanthin und guanin. Liebigs Ann Chem 1883; 221: 336-344
    PubMedSearch in Google Scholar
  • 20 Sono M, Toyoda N, Shimizu K et al. Functionalization including fluorination of nitrogen-containing compounds using electrochemical oxidation. Chem Pharm Bull 1996; 44: 1141-1145
    CrossrefPubMedSearch in Google Scholar
  • 21 Tsotinis A, Calogeropoulou T, Koufaki M et al. Synthesis and antiretroviral evaluation of new alkoxy and aryloxy phosphate derivatives of 3'-azido-3'-deoxythymidine. J Med Chem 1996; 39: 3418-3422
    CrossrefPubMedSearch in Google Scholar
  • 22 Stenkamp D, Mueller SG, Lustenberger P et al. Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds. United States Patent Apr 13 2005; PN 7: 592-358
    PubMedSearch in Google Scholar
  • 23 Huston RC, Allen WF. Caffeine derivatives. I. The 8-ethers of caffeine. J Am Chem Soc 1934; 56: 1356-1358
    CrossrefPubMedSearch in Google Scholar
  • 24 Baumann W. Die nervenkrankenfürsorge der stadt essen. Z Gesamte Neurol Psy 1913; 15: 114-121
    PubMedSearch in Google Scholar
  • 25 Legoabe LJ, Petzer A, Petzer JP. Inhibition of monoamine oxidase by selected C6-substituted chromone derivatives. Eur J Med Chem 2012; 49: 343-353
    CrossrefPubMedSearch in Google Scholar
  • 26 Novaroli L, Reist M, Favre E et al. Human recombinant monoamine oxidase B as reliable and efficient enzyme source for inhibitor screening. Bioorg Med Chem 2005; 13: 6212-6217
    CrossrefPubMedSearch in Google Scholar
  • 27 Petzer A, Harvey BH, Wegener G, et al. Azure B. a metabolite of methylene blue, is a high-potency, reversible inhibitor of monoamine oxidase. Toxicol Appl Pharm 2012; 58: 403-409
    PubMedSearch in Google Scholar
  • 28 Hubálek F, Binda C, Khalil A et al. Demonstration of isoleucine 199 as a structural determinant for the selective inhibition of human monoamine oxidase B by specific reversible inhibitors. J Biol Chem 2005; 280: 15761-15766
    CrossrefPubMedSearch in Google Scholar
  • 29 Son S-Y, Ma J, Kondou Y et al. Structure of human monoamine oxidase A at 2.2-Å resolution: the control of opening the entry for substrates/inhibitors. Proc Natl Acad Sci USA 2008; 105: 5739-5744
    CrossrefPubMedSearch in Google Scholar