title: Inhibition of monoamine oxidase by selected phenylalkylcaffeine analogues.
abstract: OBJECTIVE
  Caffeine represents a useful scaffold for the design of monoamine oxidase (MAO) type B inhibitors. Specifically, substitution on the C8 position yields structures which are high-potency MAO-B inhibitors. To explore the structure-activity relationships of MAO-B inhibition by caffeine-derived compounds, this study examines the MAO inhibitory properties of a series of phenylalkylcaffeine analogues.
  
  
  METHODS
  Employing the recombinant human enzymes, the potencies (IC50 values) by which the caffeine analogues inhibit MAO-A and MAO-B were measured. The reversibility of inhibition of a selected inhibitor was determined by measuring the recovery of enzyme activity after dilution and dialysis of enzyme-inhibitor mixtures.
  
  
  RESULTS
  The results document that the phenylalkylcaffeine analogues are reversible and selective MAO-B inhibitors with a competitive mode of inhibition. The most potent analogue, 8-(7-phenylheptyl)caffeine, exhibits IC50 values for the inhibition of MAO-A and MAO-B of 3.01 μm and 0.086 μm, respectively. Increasing the length of the alkyl side chain leads to enhanced MAO-A and MAO-B inhibitory potency while introduction of a carbonyl group reduces MAO-B inhibitory potency.
  
  
  CONCLUSIONS
  Phenylalkylcaffeines represent a new class of high-potency MAO-B inhibitors with the longer alkyl side chains yielding enhanced inhibitory activity. Such compounds may represent useful leads for the development of anti-parkinsonian therapies.
authors: Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.
authors: Anél
authors: A
authors: Petzer
authors: Paul
authors: P
authors: Grobler
authors: Jacobus J
authors: JJ
authors: Bergh
authors: Jacobus P
authors: JP
authors: Petzer
mesh_terms: D002110:Caffeine / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D008996:Monoamine Oxidase Inhibitors; D002110:Caffeine; D008995:Monoamine Oxidase
keywords: caffeine; competitive; monoamine oxidase; reversible inhibition; structure-activity relationship