Structure-activity relationships in the inhibition of monoamine oxidase B by 1-methyl-3-phenylpyrroles

Modupe O. Ogunrombi, Sarel F. Malan, Gisella Terre'Blanche, Neal Castagnoli, Jacobus J. Bergh, Jacobus P. Petzer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

1-Methyl-3-phenyl-3-pyrrolines are structural analogues of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and like MPTP are selective substrates of monoamine oxidase B (MAO-B). As part of an ongoing investigation into the substrate properties of various 1-methyl-3-phenyl-3-pyrrolinyl derivatives, it is shown in the present study that their respective MAO-B catalyzed oxidation products act as reversible competitive inhibitors of the enzyme. The most potent inhibitor among the oxidation products considered was 1-methyl-3-(4-trifluoromethylphenyl)pyrrole with an enzyme-inhibitor dissociation constant (Ki value) of 1.30 μM. The least potent inhibitor was found to be 1-methyl-3-phenylpyrrole with a Ki value of 118 μM. The results of an SAR study established that the potency of MAO-B inhibition by the 1-methyl-3-phenylpyrrolyl derivatives examined here is dependent on the Taft steric parameter (Es) and Swain-Lupton electronic constant (F) of the substituents attached to C-4 of the phenyl ring. Electron-withdrawing substituents with a large degree of steric bulkiness appear to enhance inhibition potency. Potency was also found to vary with the substituents at C-3, again with Es and F being the principal substituent descriptors.

Original languageEnglish
Pages (from-to)2463-2472
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number5
DOIs
Publication statusPublished - 1 Mar 2008
Externally publishedYes

Keywords

  • 1-Methyl-3-phenylpyrrole
  • Competitive inhibition
  • Monoamine oxidase B
  • Reversible inhibitors
  • Structure-activity relationship

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