Time-dependent slowly-reversible inhibition of monoamine oxidase A by N-substituted 1,2,3,6-tetrahydropyridines |
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Authors: | Wichitnithad Wisut O'Callaghan James P Miller Diane B Train Brian C Callery Patrick S |
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Institution: | aDepartment of Basic Pharmaceutical Sciences and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA;bDepartment of Pharmaceutical Technology (International Program), Chulalongkorn University, Bangkok 10330, Thailand;cCenters for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV 26506, USA |
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Abstract: | A novel class of N-substituted tetrahydropyridine derivatives was found to have multiple kinetic mechanisms of monoamine oxidase A inhibition. Eleven structurally similar tetrahydropyridine derivatives were synthesized and evaluated as inhibitors of MAO-A and MAO-B. The most potent MAO-A inhibitor in the series, 2,4-dichlorophenoxypropyl analog 12, displayed time-dependent mixed noncompetitive inhibition. The inhibition was reversed by dialysis, indicating reversible enzyme inhibition. Evidence that the slow-binding inhibition of MAO-A with 12 involves a covalent bond was gained from stabilizing a covalent reversible intermediate product by reduction with sodium borohydride. The reduced enzyme complex was not reversible by dialysis. The results are consistent with slowly reversible, mechanism-based inhibition. Two tetrahydropyridine analogs that selectively inhibited MAO-A were characterized by kinetic mechanisms differing from the kinetic mechanism of 12. As reversible inhibitors of MAO-A, tetrahydropyridine analogs are at low risk of having an adverse effect of tyramine-induced hypertension. |
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Keywords: | InChIKeys: YIOOFSFSYIFVGA-UHFFFAOYSA-N RFGSGIYDYZAVKP-UHFFFAOYSA-N PATARMBKZNQOFI-UHFFFAOYSA-N ZCNRONWKKLYGKC-UHFFFAOYSA-N WOKZGPAOFQHBRB-UHFFFAOYSA-N QUOQRHUEAFIBQT-UHFFFAOYSA-N PEWKBQSNFNCVBM-UHFFFAOYSA-N SIRJFTFGHZXRRZ-UHFFFAOYSA-N NLNNODLEXBFJDM-UHFFFAOYSA-N DBDVAKGHPZJLTH-UHFFFAOYSA-N BDBKTQWAORGGJI-UHFFFAOYSA-N |
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