Improved Muscarinic Antagonists as Anticholinesterase Antidotes
Final rept. 15 Jun 85-14 Dec 87,
SRI INTERNATIONAL MENLO PARK CA
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Muscarinic antagonists play an important role in anticholinesterase agent therapy by reducing the response of muscarinic receptors to acetylcholine, acting synergistically with cholinesterase reactivators. Therapy with antagonists such as atropine is difficult to manage because of the toxicity of these compounds, atropine antagonizes the receptor whether or not acetylcholine levels are elevated. Our approach to the development of a better antidote is to design a molecule whose concentration and resulting muscarinic antagonist activity is controlled by the degree of cholinesterase inhibition, and thus by the need for the drug. This is accomplished by incorporating into the same molecule features that confer muscarinic antagonism and susceptibility to hydrolysis by cholinesterase. Such compounds should be rapidly degraded by cholinesterase to inactive products in a normal system, but should remain active when cholinesterase has been inhibited. As the cholinesterase activity recovers, the compounds should again be hydrolyzed. The proper combination of muscarinic antagonism and susceptibility to cholinesterase hydrolysis should allow these compounds to be used at higher doses with fewer side effects.
- Medicine and Medical Research