title: Synthesis and evaluation of a set of para-substituted 4-phenylpiperidines and 4-phenylpiperazines as monoamine oxidase (MAO) inhibitors.
abstract: A series of para-substituted 4-phenylpiperidines/piperazines have been synthesized and their affinity to recombinant rat cerebral cortex monoamine oxidases A (MAO A) and B (MAO B) determined. Para-substituents with low dipole moment increased the affinity to MAO A, whereas groups with high dipole moment yielded compounds with no or weak affinity. In contrast, the properties affecting MAO B affinity were the polarity and bulk of the para-substituent, with large hydrophobic substituents producing compounds with high MAO B affinity. In addition, these compounds were tested in freely moving rats and the effect on the post-mortem neurochemistry was measured. A linear correlation was demonstrated between the affinity for MAO A, but not MAO B, and the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) in the striatum.
authors.affiliation: NeuroSearch Sweden AB, Arvid Wallgrens Backe 20, S-413 46 Göteborg, Sweden. fpe@neurosearch.se
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pettersson
authors.forename: Peder
authors.initials: P
authors.lastname: Svensson
authors.forename: Susanna
authors.initials: S
authors.lastname: Waters
authors.forename: Nicholas
authors.initials: N
authors.lastname: Waters
authors.forename: Clas
authors.initials: C
authors.lastname: Sonesson
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001555:Benzene Derivatives; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D010879:Piperazines; D010880:Piperidines; D015102:3,4-Dihydroxyphenylacetic Acid; D008995:Monoamine Oxidase; C001746:3-methoxytyramine; D004298:Dopamine