title: Structure-activity relationships for inhibition of human cholinesterases by alkyl amide phenothiazine derivatives.
abstract: Several lines of evidence indicate that inhibition of butyrylcholinesterase (BuChE) is important in the treatment of certain dementias. Further testing of this concept requires inhibitors that are both BuChE-selective and robust. N-alkyl derivatives (2, 3, 4) of phenothiazine (1) have previously been found to inhibit only BuChE in a mechanism involving pi-pi interaction between the phenothiazine tricyclic ring system and aromatic residues in the active site gorge. To explore features of phenothiazines that affect the selectivity and potency of BuChE inhibition, a series of N-carbonyl derivatives (5-25) was synthesized and examined for the ability to inhibit cholinesterases. Some of the synthesized derivatives also inhibited AChE through a different mechanism involving carbonyl interaction within the active site gorge. Binding of these derivatives takes place within the gorge, since this inhibition disappears when the molecular volume of the derivative exceeds the estimated active site gorge volume of this enzyme. In contrast, BuChE, with a much larger active site gorge, exhibited inhibition that increased directly with the molecular volumes of the derivatives. This study describes two distinct mechanisms for binding phenothiazine amide derivatives to BuChE and AChE. Molecular volume was found to be an important parameter for BuChE-specific inhibition.
authors.affiliation: Department of Medicine (Neurology), Dalhousie University, Halifax, Nova Scotia, Canada. sultan.darvesh@dal.ca
authors.forename: Sultan
authors.initials: S
authors.lastname: Darvesh
authors.forename: Robert S
authors.initials: RS
authors.lastname: McDonald
authors.forename: Andrea
authors.initials: A
authors.lastname: Penwell
authors.forename: Sarah
authors.initials: S
authors.lastname: Conrad
authors.forename: Katherine V
authors.initials: KV
authors.lastname: Darvesh
authors.forename: Diane
authors.initials: D
authors.lastname: Mataija
authors.forename: Geraldine
authors.initials: G
authors.lastname: Gomez
authors.forename: Angela
authors.initials: A
authors.lastname: Caines
authors.forename: Ryan
authors.initials: R
authors.lastname: Walsh
authors.forename: Earl
authors.initials: E
authors.lastname: Martin
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000187:drug effects / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010640:Phenothiazines / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D010640:Phenothiazines; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase