title: New pyrrole inhibitors of monoamine oxidase: synthesis, biological evaluation, and structural determinants of MAO-A and MAO-B selectivity.
abstract: A series of new pyrrole derivatives have been synthesized and evaluated for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. N-Methyl,N-(benzyl),N-(pyrrol-2-ylmethyl)amine (7) and N-(2-benzyl),N-(1-methylpyrrol-2-ylmethyl)amine (18) were the most selective MAO-B (7, SI = 0.0057) and MAO-A (18, SI = 12500) inhibitors, respectively. Docking and molecular dynamics simulations gave structural insights into the MAO-A and MAO-B selectivity. Compound 18 forms an H-bond with Gln215 through its protonated amino group into the MAO-A binding site. This H-bond is absent in the 7/MAO-A complex. In contrast, compound 7 places its phenyl ring into an aromatic cage of the MAO-B binding pocket, where it forms charge-transfer interactions. The slightly different binding pose of 18 into the MAO-B active site seems to be forced by a bulkier Tyr residue, which replaces a smaller Ile residue present in MAO-A.
authors.affiliation: Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Regina
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
authors.forename: Marino
authors.initials: M
authors.lastname: Artico
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Olivia
authors.initials: O
authors.lastname: Befani
authors.forename: Paola
authors.initials: P
authors.lastname: Turini
authors.forename: Enzo
authors.initials: E
authors.lastname: Agostinelli
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000201:enzymology / Q000648:ultrastructure; D002417:Cattle; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001596:Benzylamines; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; C518983:N-(2-benzyl),N-(1-methylpyrrol-2-ylmethyl)amine; C518982:N-methyl,N-(benzyl),N-(pyrrol-2-ylmethyl)amine; D011758:Pyrroles; D008995:Monoamine Oxidase