Accession Number : ADA586023


Title :   Inhibitor Profile of bis(n)-tacrines and N-methylcarbamates on Acetylcholinesterase from Rhipicephalus (Boophilus) Microplus and Phlebotomus Papatasi


Descriptive Note : Journal article


Corporate Author : DEPARTMENT OF AGRICULTURE KERRVILLE TX AGRICULTURAL RESEARCH SERVICE


Personal Author(s) : Swale, Daniel R ; Tong, Fan ; Temeyer, Kevin B ; Li, Andrew ; Lam, Polo C ; Totrov, Maxim M ; Carlier, Paul R ; Leon, Adalberto A de ; Bloomquist, Jeffrey R


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a586023.pdf


Report Date : 28 Mar 2013


Pagination or Media Count : 10


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 from Bm (BmAChE1) and Pp (PpAChE) compared to human and bovine AChE, in order to identify divergent pharmacology that might lead to selective inhibitors. Results indicate that BmAChE has low sensitivity (IC50 = 200 lM) toward tacrine, a monovalent catalytic site inhibitor with sub micromolar blocking potency in all previous species tested. Similarly, a series of bis(n)-tacrine dimer series, bivalent inhibitors and peripheral site AChE inhibitors possess poor potency toward BmAChE. 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 and PpAChE 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 for BmAChE1 and PpAChE over human AChE, and a mouse oral LD50 of 1500 mg/kg, thus providing an excellent new lead for vector control.


Descriptors :   *ACETYLCHOLINESTERASE , *DISEASE VECTORS , *INSECTICIDES , ARTHROPODA , CARBAMATES , INHIBITORS , MAMMALS , RESISTANCE , TICKBORNE DISEASES , TICKS , TOXICITY


Subject Categories : Agricultural Chemistry
      Biochemistry
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE