Structure-Activity Relationships of Agents Modifying Cholinergic Transmissions
Annual progress rept. no. 1, 1 Sep 1982-31 Aug 1983
IOWA UNIV IOWA CITY
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The purpose of this research is the synthesis and biological evaluation of analogs of hemicholinium HC-3. These are agents which decrease the ability of cholinergic neurones to synthesize acetylcholine. The long-range goal of this research is to develop compounds which can be used to antidote excess acetylcholine within a cholinergic synapse. Some possible approaches are 1 decrease the content of acetylcholine within the cholinergic neurone by interfering with synthesis, 2 desensitizing cholinergic receptors at post- synaptic sites, 3 decreasing the release of acetylcholine from the neurone by stabilizing the membrane or via pre-synaptic receptors which when activated will diminish the amount of acetylcholine released into the synapse. Thus far 3 agents have been prepared and evaluated for activity. Two of the agents, which are quarternary amines, approximate HC-3 in activity and the tertiary amine derivative is approximately 1500th as active as HC-3. The latter agent is the first active non-quarternary amine to be reported. The biological assay procedures have been developed to evaluate these agents. Keywords High performance liquid chromatography Incubation Caudate nucleus Rats Rabbits Nerve-gastrochemisumuscle In viro analysis Neuro-muscular blocking Phrenic nerve-diaphragm muscle In vitro analysis and Neuromuscular transmission.