title: 8-Aryl- and alkyloxycaffeine analogues as inhibitors of monoamine oxidase.
abstract: Recently it was reported that a series of 8-benzyloxycaffeine analogues are potent reversible inhibitors of human monoamine oxidase (MAO) A and B. In an attempt to discover additional C8 oxy substituents of caffeine that lead to potent MAO inhibition, a series of related 8-aryl- and alkyloxycaffeine analogues were synthesized and their MAO-A and -B inhibition potencies were compared to those of the 8-benzyloxycaffeines. The results document that while the 8-substituted-oxycaffeine analogues inhibited both human MAO isoforms, they displayed a high degree of selectivity for MAO-B. 8-(3-Phenylpropoxy)caffeine, 8-(2-phenoxyethoxy)caffeine and 8-[(5-methylhexyl)oxy]caffeine were found to be the especially potent MAO-B inhibitors with IC(50) values ranging from 0.38 to 0.62 μM. These inhibitors are therefore 2.5-4.6 fold more potent MAO-B inhibitors than is 8-benzyloxycaffeine (IC(50) = 1.77 μM). It is also demonstrated that, analogous to 8-benzyloxycaffeine, halogen substitution on the phenyl ring of the C8 substituent significantly enhances MAO binding affinity. For example, the most potent MAO-B inhibitor of the present series is 8-[2-(4-bromophenoxy)ethoxy]caffeine with an IC(50) value of 0.166 μM. This study also reports possible binding orientations of selected oxy caffeines within the active site cavities of MAO-A and MAO-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: Jacobus J
authors.initials: JJ
authors.lastname: Bergh
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
mesh_terms: D000478:Alkylation; D000818:Animals; D001665:Binding Sites; D002110:Caffeine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D006219:Halogens / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007735:Kynuramine / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000503:physiopathology; D011485:Protein Binding / Q000187:drug effects*; D011618:Psychotic Disorders / Q000188:drug therapy / Q000503:physiopathology; D011619:Psychotropic Drugs / Q000138:chemical synthesis* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D006219:Halogens; D008996:Monoamine Oxidase Inhibitors; D011619:Psychotropic Drugs; D011994:Recombinant Proteins; D007735:Kynuramine; D002110:Caffeine; D008995:Monoamine Oxidase