title: Novel tacrine analogues for potential use against Alzheimer's disease: potent and selective acetylcholinesterase inhibitors and 5-HT uptake inhibitors.
abstract: Several novel analogues of tacrine have been synthesized and tested for their ability to inhibit acetylcholinesterase, butyrylcholinesterase, and neuronal uptake of 5-HT (serotonin) and noradrenaline. Changes in the size of the carbocyclic ring of tacrine produced modest potency against cholinesterase enzymes. Addition of a fourth ring resulted in compounds with marked selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase (BChE): e.g. 6-amino-4,5-benzo-5H-cyclopenta[1,2-b]-quinoline (14a) had an IC50 of 0.35 microM against AChE and 3.1 microM against BChE. Some tetracyclic compounds are 100-400 times more active than tacrine as inhibitors of neuronal uptake of serotonin, in particular 13-amino-6,7-dihydro-5H-benzo-[3,4]cyclohepta[1,2-b]quinoline (18), which had an IC50 of 20 nM. These compounds would be expected to facilitate both cholinergic and monoaminergic transmission. They should be worth investigating in models of memory impairment.
authors.affiliation: Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, U.K.
authors.forename: M T
authors.initials: MT
authors.lastname: McKenna
authors.forename: G R
authors.initials: GR
authors.lastname: Proctor
authors.forename: L C
authors.initials: LC
authors.lastname: Young
authors.forename: A L
authors.initials: AL
authors.lastname: Harvey
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects*; D000544:Alzheimer Disease / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D013619:Tacrine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000110:Acetylcholinesterase; D002800:Cholinesterase Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors; D013619:Tacrine