title: Inhibition of monoamine oxidase by pirlindole analogues: 3D-QSAR and CoMFA analysis.
abstract: A series of pyrazinocarbazoles, analogues of short acting antidepressant pirlindole (2,3,3a,4,5,6-hexahydro-8-methyl-1H-pyrazino[3,2,1-j,k]carbazole hydrochloride), were tested as inhibitors of monoamine oxidase A (MAO-A) and B (MAO-B). Rigid analogues exhibited potent and selective inhibition of MAO-A and have size limits (X:Y:Z) of 13.0 x 7.0 x 4.4 A. Besides MAO-A inhibition flexible analogues also demonstrated potent inhibition of MAO-B and in contrast to rigid analogues their inhibitory activity did not show the dependence on these sizes. The qualitative information (steric and electrostatic coefficients) from the 3D-QSAR with CoMFA models for MAO-A and -B are different, and this information can be used to determine the structural features influencing inhibitor selectivity.
authors.affiliation: Laboratory of Biochemistry, Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: A E
authors.initials: AE
authors.lastname: Medvedev
authors.forename: A V
authors.initials: AV
authors.lastname: Veselovsky
authors.forename: V I
authors.initials: VI
authors.lastname: Shvedov
authors.forename: O V
authors.initials: OV
authors.lastname: Tikhonova
authors.forename: T A
authors.initials: TA
authors.lastname: Moskvitina
authors.forename: O A
authors.initials: OA
authors.lastname: Fedotova
authors.forename: L N
authors.initials: LN
authors.lastname: Axenova
authors.forename: N S
authors.initials: NS
authors.lastname: Kamyshanskaya
authors.forename: A Z
authors.initials: AZ
authors.lastname: Kirkel
authors.forename: A S
authors.initials: AS
authors.lastname: Ivanov
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000737:chemistry* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002227:Carbazoles; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase; C009830:pirlindole