title: Selectivity of phenothiazine cholinesterase inhibitors for neurotransmitter systems.
abstract: Synthetic derivatives of phenothiazine have been used for over a century as well-tolerated drugs against a variety of human ailments from psychosis to cancer. This implies a considerable diversity in the mechanisms of action produced by structural changes to the phenothiazine scaffold. For example, chlorpromazine treatment of psychosis is related to its interaction with dopaminergic receptors. On the other hand, antagonistic action of such drugs on cholinergic receptor systems would be counter-productive for treatment of Alzheimer's disease. In a search for phenothiazines that are inhibitors of cholinesterases, especially butyrylcholinesterase, with potential to treat Alzheimer's disease, we wished to ascertain that such molecules could be devoid of neurotransmitter receptor interactions. To that end, a number of our synthetic N-10-carbonyl phenothiazine derivatives, with cholinesterase inhibitory activity, were tested for interaction with a variety of neurotransmitter receptor systems. We demonstrate that phenothiazines can be prepared without significant neurotransmitter receptor interactions while retaining high potency as cholinesterase ligands for treatment of Alzheimer's disease.
authors.affiliation: Department of Medicine (Neurology and Geriatric Medicine), Dalhousie University, 5850 College Street, Halifax, Nova Scotia, Canada B3H 4R2. sultan.darvesh@dal.ca
authors.forename: Sultan
authors.initials: S
authors.lastname: Darvesh
authors.forename: Ian R
authors.initials: IR
authors.lastname: Macdonald
authors.forename: Earl
authors.initials: E
authors.lastname: Martin
mesh_terms: D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D010640:Phenothiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D010640:Phenothiazines; D017981:Receptors, Neurotransmitter; D002091:Butyrylcholinesterase; C031637:phenothiazine