Potential therapeutic effects of oximes

Abstract

The nerve agent, Soman, is a difficult intoxication to treat as soman-inhibited acetylcholinesterase becomes resistant to oxime reactivation within minutes. High doses of HI-6 protect against soman, even after aging has set in, through non-reactivation therapeutic effects. The focus of this thesis involved synthesising a series of structurally-related O-alkyl substituted 2-PAM derivatives to derive therapeutic a??directa?? effects. Some of the resulting oxime derivatives attenuated soman-induced spike in acetylcholine efflux and protected against neuropathology during soman poisoning. The compound was observed to retard the dissociation of NMS from muscarinic receptor in an allosteric manner, thus stabilising the anticholinergic-muscarinic receptor complex. The thesis also evaluated the muscarinic agonist properties of two parallel series of tropinone and quinuclidinone oximes and reaffirm the importance for rigidity in the basic nitrogen ring system for muscarinic agonist activity. The nature of the azabicyclo ring was determined to affect the muscarinic receptor subtype selectivity and agonist efficacy.