TY - JOUR
T1 - Structure-activity relationships in the inhibition of monoamine oxidase B by 1-methyl-3-phenylpyrroles
AU - Ogunrombi, Modupe O.
AU - Malan, Sarel F.
AU - Terre'Blanche, Gisella
AU - Castagnoli, Neal
AU - Bergh, Jacobus J.
AU - Petzer, Jacobus P.
N1 - Funding Information:
The NMR and MS spectra were recorded by André Joubert, Johan Jordaan, and Louis Fourie of the SASOL Centre for Chemistry, North-West University. This work was supported by grants from the National Research Foundation and the Medical Research Council, South Africa.
PY - 2008/3/1
Y1 - 2008/3/1
N2 - 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.
AB - 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.
KW - 1-Methyl-3-phenylpyrrole
KW - Competitive inhibition
KW - Monoamine oxidase B
KW - Reversible inhibitors
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=40749116837&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2007.11.059
DO - 10.1016/j.bmc.2007.11.059
M3 - Article
C2 - 18065227
AN - SCOPUS:40749116837
SN - 0968-0896
VL - 16
SP - 2463
EP - 2472
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 5
ER -