title: Inhibitor profile ofbis(n)-tacrinesand N-methylcarbamates on acetylcholinesterase fromRhipicephalus (Boophilus) microplusandPhlebotomus papatasi.
abstract: The cattle tick,Rhipicephalus (Boophilus) microplus(Bm), and the sand fly,Phlebotomus papatasi (Pp),are disease vectors to cattle and humans, respectively. The purpose of this study was to characterize the inhibitor profile of acetylcholinesterases fromBm(BmAChE1) andPp(PpAChE) compared to human and bovine AChE, in order to identify divergent pharmacology that might lead to selective inhibitors. Results indicate thatBmAChE has low sensitivity (IC50= 200 μM) toward tacrine, a monovalent catalytic site inhibitor with sub micromolar blocking potency in all previous species tested. Similarly, a series ofbis(n)-tacrine dimer series, bivalent inhibitors and peripheral site AChE inhibitors possess poor potency towardBmAChE. Molecular homology models suggest the rBmAChE enzyme possesses a W384F orthologous substitution near the catalytic site, where the larger tryptophan side chain obstructs the access of larger ligands to the active site, but functional analysis of this mutation suggests it only partially explains the low sensitivity to tacrine. In addition,BmAChE1 andPpAChE have low nanomolar sensitivity to some experimental carbamate anticholinesterases originally designed for control of the malaria mosquito,Anopheles gambiae. One experimental compound, 2-((2-ethylbutyl)thio)phenyl methylcarbamate, possesses >300-fold selectivity forBmAChE1 andPpAChE over human AChE, and a mouse oral LD50of >1500 mg/kg, thus providing an excellent new lead for vector control.
authors.affiliation: Department of Entomology and Nematology, Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32611, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Swale
authors.forename: Fan
authors.initials: F
authors.lastname: Tong
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Temeyer
authors.forename: Andrew
authors.initials: A
authors.lastname: Li
authors.forename: Polo C-H
authors.initials: PC
authors.lastname: Lam
authors.forename: Maxim M
authors.initials: MM
authors.lastname: Totrov
authors.forename: Paul R
authors.initials: PR
authors.lastname: Carlier
authors.forename: Adalberto A
authors.initials: AA
authors.lastname: Pérez de León
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Bloomquist
keywords: Leishmaniasis; cattle fever; insecticides; sandfly; selectivity; southern cattle tick