title: Inhibition of monoamine oxidase by 8-benzyloxycaffeine analogues.
abstract: Based on recent reports that several (E)-8-styrylcaffeinyl analogues are potent reversible inhibitors of monoamine oxidase B (MAO-B), a series of 8-benzyloxycaffeinyl analogues were synthesized and evaluated as inhibitors of baboon liver MAO-B and recombinant human MAO-A and -B. The 8-benzyloxycaffeinyl analogues were found to inhibit reversibly both MAO isoforms with enzyme-inhibitor dissociation constants (K(i) values) ranging from 0.14 to 1.30 microM for the inhibition of human MAO-A, and 0.023-0.59 microM for the inhibition of human MAO-B. The most potent MAO-A inhibitor was 8-(3-methylbenzyloxy)caffeine while 8-(3-bromobenzyloxy)caffeine was the most potent MAO-B inhibitor. The analogues inhibited human and baboon MAO-B with similar potencies. A quantitative structure-activity relationship (QSAR) study indicated that the MAO-B inhibition potencies of the 8-benzyloxycaffeinyl analogues are dependent on the Hansch lipophilicity (pi) and Hammett electronic (sigma) constants of the substituents at C-3 of the benzyloxy ring. Electron-withdrawing substituents with a high degree of lipophilicity enhance inhibition potency. These results are discussed with reference to possible binding orientations of the inhibitors within the active site cavities of MAO-A and -B.
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Belinda
authors.initials: B
authors.lastname: Strydom
authors.forename: Sarel F
authors.initials: SF
authors.lastname: Malan
authors.forename: Neal
authors.initials: N
authors.lastname: Castagnoli
authors.forename: Jacobus J
authors.initials: JJ
authors.lastname: Bergh
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
mesh_terms: D000818:Animals; D002110:Caffeine / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010215:Papio; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D008996:Monoamine Oxidase Inhibitors; D002110:Caffeine; D008995:Monoamine Oxidase