1. The actions of
oximes and related compounds on the
nicotinic acetylcholine receptor ion channel at the adult mouse muscle endplate were investigated by use of single-channel recording techniques. The aim of the study was to determine whether the channel-blocking properties of the compounds could contribute to their therapeutic effectiveness against
soman poisoning in vitro. 2. Therapeutic effectiveness was assessed in guinea-pig phrenic nerve-hemidiaphragm preparations by measuring the degree of recovery of neuromuscular function produced by the compounds following
poisoning by
soman. A number of the compounds, including some which lacked the
oxime group, produced a significant recovery of neuromuscular function which was unrelated to
acetylcholinesterase (AChE) reactivation; this was reversed by washing off the compound, and was therefore attributed to a direct pharmacological action on the muscle. 3. Single channel recordings showed that some of the compounds blocked open
nicotinic receptor ion channels in preparations of mouse muscle fibres. The compounds which showed the greatest direct pharmacological actions in diaphragms produce a very fast, flickering blockade of the channels. Several quantitative measures of channel-blocking activity correlated very well with the direct pharmacological action. Furthermore, for two compounds studied in greater detail, the direct action and channel-blocking showed similar concentration-response relationships. 4. The results of this study indicate that the direct pharmacological action of
oximes and their analogues against neuromuscular blockade by
soman in vitro is due to their channel-blocking activity. The direct action does not correlate well with protection against
soman poisoning in vivo, however, which suggests that additional non-reactivating properties of these compounds, at sites other than the neuromuscular junction, may also be important for their therapeutic effectiveness.