title: Differential binding of phenothiazine urea derivatives to wild-type human cholinesterases and butyrylcholinesterase mutants.
abstract: A series of N-10 urea derivatives of phenothiazine was synthesized and each compound was evaluated for its ability to inhibit human cholinesterases. Most were specific inhibitors of BuChE. However, the potent inhibitory effects on both cholinesterases of one sub-class, the cationic aminoureas, provide an additional binding mechanism to cholinesterases for these compounds. The comparative effects of aminoureas on wild-type BuChE and several BuChE mutants indicate a binding process involving salt linkage with the aspartate of the cholinesterase peripheral anionic site. The effect of such compounds on cholinesterase activity at high substrate concentration supports ionic interaction of aminoureas at the peripheral anionic site.
authors.affiliation: Department of Medicine (Neurology), Dalhousie University, Halifax, Nova Scotia, Canada; Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
authors.forename: Sultan
authors.initials: S
authors.lastname: Darvesh
authors.affiliation: Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Pottie
authors.affiliation: Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
authors.forename: Katherine V
authors.initials: KV
authors.lastname: Darvesh
authors.affiliation: Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
authors.forename: Robert S
authors.initials: RS
authors.lastname: McDonald
authors.affiliation: Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Ryan
authors.initials: R
authors.lastname: Walsh
authors.affiliation: Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Conrad
authors.affiliation: Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Penwell
authors.affiliation: Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
authors.forename: Diane
authors.initials: D
authors.lastname: Mataija
authors.affiliation: Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
authors.forename: Earl
authors.initials: E
authors.lastname: Martin
mesh_terms: D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002802:Cholinesterases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009154:Mutation; D010640:Phenothiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D010640:Phenothiazines; D014508:Urea; D002091:Butyrylcholinesterase; D002802:Cholinesterases