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Inhibition of monoamine oxidase by clorgyline analogues

  • E. M. O’Brien
  • K. F. Tipton
  • M. Meroni
  • P. Dostert
Conference paper
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 41)

Summary

N-Methyl-N-propargyl-3-(4-phenoxy)phenoxypropylamine, an analogue of the MAO-A-selective irreversible inhibitor clorgyline in which the 2,4-dichloro- substitution in clorgyline was replaced by a 2-H atom and a 4-phenoxy group, has been synthesised and assessed as an inhibitor of monoamine oxidase (MAO). This compound proved to be a time-dependent irreversible inhibitor of both MAO-A and -B. However, unlike clorgyline, it was selective towards MAO-B, both in its initial, non-covalent, binding to the enzyme and as an irreversible inhibitor. In order to assess the influence of side-chain length on inhibitory potency, analogues were synthesised in which the side-chain was reduced to 2 CH2 units (N-methyl-N-propargyl-2-(4-phenoxy)phenoxyethylamine) or increased to 4 CH2 units (N-methyl-N-propargyl-4-(4-phenoxy)phenoxybutylamine). Both these compounds were also time-dependent irreversible inhibitors with selectivity towards MAO-B. In the case of the initial, non-covalent, inhibition all these compounds were competitive inhibitors of MAO-A, with respect to the amine substrate, and the affinity for inhibitor binding increased with carbon chain length. In contrast the compounds were all mixed inhibitors of MAO-B. The competitive element of this inhibition (measured by Kis) was similar for the 2 and 3 carbon-chain compounds but decreased markedly when the chain-length was increased to 4 carbons. The uncompetitive inhibition (measured by Kii) decreased as the carbon chain-length was increased from 2 to 3, but there was no significant further change when the length was increased to 4 carbons. The time-dependent irreversible inhibition (measured as the IC50 values after 60 min enzyme-inhibitor preincubation) showed that the potency towards MAO-A increased when the side-chain length was increased from 2 to 3 carbons but that there was no significant difference between the 3 and 4 carbon-chain compounds. In the case of MAO-B inhibition, the 2 and 3 carbon-chain compounds had similar inhibitory potencies but this increased substantially when the chain length was increased to 4 carbons. The significance of the inhibitory behaviour of these compounds is discussed in terms of the structure-activity relationships of mechanism-based irreversible MAO inhibitors.

Keywords

Monoamine Oxidase Inhibitory Potency Irreversible Inhibitor Isopropyl Ether Uncompetitive Inhibition 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • E. M. O’Brien
    • 1
  • K. F. Tipton
    • 1
  • M. Meroni
    • 2
  • P. Dostert
    • 2
  1. 1.Department of BiochemistryTrinity CollegeDublin 2Ireland
  2. 2.Research and Development-Erbamont GroupFarmitalia Carlo ErbaMilanItaly

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