Bifunctional compounds eliciting anti-inflammatory and anti-cholinesterase activity as potential treatment of nerve and blister chemical agents poisoning.
Studies cited by Cowan et al. [J. Appl. Toxicol. 23, 177 (2003)] indicate existence of inflammatory and cholinergic pathways in both nerve agents and sulfur mustard (HD) injury. Increase in AChE synthesis and neurite extension was noted after exposure to HD [K.W. Lanks et al., Exp. Cell Res. 355 (1975)]. Moreover, anti-inflammatory drugs reduce the dermal, respiratory and ocular damage caused by exposure to HD. On the other hand, recent studies have noted the involvement of neuro-inflammatory processes during exposure to the nerve agents sarin or soman [Cowan et al., 2003]. The use of various anti-inflammatory drugs in addition to the classical antidotal drugs (e.g. atropine and oximes) caused decrease in certain toxic symptoms and inflammation-induced brain damage. Our new bifunctional drugs (Scheme 1) are based on CNS-permeable molecular combination of pseudo-reversible AChE inhibitor (pyridostigmine, PYR) coupled via a hydrophobic spacer (octyl or decyl hydrocarbon chain) to a non-steroidal anti-inflammatory drug (NSAID) such as Ibuprofen or Diclofenac (Scheme 1). This study evaluates the efficacy of certain bifunctional compounds against HD and soman poisoning in mice in vivo.
Division of Medicinal Chemistry, Israel Institute for Biological Research, Ness Ziona 74100, Israel.
Gabi
G
Amitai
Rachel
R
Adani
Eliezer
E
Fishbein
Haim
H
Meshulam
Ido
I
Laish
Schlomit
S
Dachir
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use*; D001768:Blister / Q000139:chemically induced* / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D002802:Cholinesterases / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D020258:Neurotoxicity Syndromes / Q000188:drug therapy*; D012999:Soman / Q000633:toxicity; D015996:Survival Rate
D000893:Anti-Inflammatory Agents; D002800:Cholinesterase Inhibitors; D012999:Soman; D002802:Cholinesterases