New antimuscarinic agents for improved treatment of poisoning by cholinesterase inhibitors. Annual progress report No. 1, 1 November 1982-31 October 1983
The object of this project is to find a more effective antimuscarinic agent than atropine for use as an antidote for poisoning by organophosphate cholinesterase inhibitors. To start this search, 22 structurally-diverse antimuscarinic agents have been selected for initial testing. These compounds are to be evaluated for peripheral and central antimuscarinic activity in a variety of in vitro and in vivo tests in addition to determining their effectiveness as antidotes (in combination with an oxime reactivator) for poisoning by soman. Fifteen of the compounds have now been evaluated for ability to block acetylcholine-induced contractions in guinea pig intestinal smooth muscle compared to atropine. Ability to displace radiolabeled quinuclidinyl benzilate from muscarinic receptors of mouse brain homogenate has been determined for atropine, scopolamine and 19 of the compounds. Several of these compounds have a relatively stronger affinity for brain than for intestinal muscarinic receptors. Atropine, scopolamine and 12 of the compounds have also been examined as inhibitors of tremors induced by oxotremorine in mice. Two of the compounds are much more potent than atropine. None of the compounds have been tested as yet as antidotes for soman poisoning. Samples of the test compounds are being sent to the Medical Research Institute of Chemical Defense for evaluation of this property.
- Research Organization:
- Virginia Commonwealth Univ., Richmond, VA (United States). Dept. of Medicinal Chemistry
- OSTI ID:
- 6957411
- Report Number(s):
- AD-B-124518/2/XAB; CNN: DAMD17-83-C-3026
- Country of Publication:
- United States
- Language:
- English
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