Differential binding of phenothiazine urea derivatives to wild-type human cholinesterases and butyrylcholinesterase mutants.
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.
Darvesh
Sultan
S
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.
Pottie
Ian R
IR
Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
Darvesh
Katherine V
KV
Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
McDonald
Robert S
RS
Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
Walsh
Ryan
R
Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada.
Conrad
Sarah
S
Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
Penwell
Andrea
A
Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
Mataija
Diane
D
Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
Martin
Earl
E
Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada.
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*
D010640:Phenothiazines; D014508:Urea; D002091:Butyrylcholinesterase; D002802:Cholinesterases