Acetylcholine suppression and potential benefit against anticholinesterase poisoning. Annual report No. 2, 1 July 1983-30 June 1984
A new series of compounds containing the quinuclidine moiety has been synthesized and tested as inhibitors of brain choline acetyltransferase (ChAT) or as inhibitors of high affinity choline uptake (HAChU). The tertiary quinuclidine was incorporated because of the potency it confers on anticholinergic compounds and antimuscarinic drugs, such as quinuclidinylbenzilate (QNB). Structure-activity studies indicate that ChAT inhibition and lipophilicity show a direct correlation and that some of the structure-activity relationships previously proposed (2) need to be modified to fit new insights gained from studies with the brain ChAT. The effectiveness of the quaternary HAChU inhibitor, acetylseco-hemicholinium (AcSeco HC) to block choline uptake and interfere with acetylcholine (ACh) synthesis served as a basis for in vivo protection studies versus soman. As an adjunct to atropine and oxime, the results obtained point to the need for HAChU inhibitors with pharmacokinetic properties which will permit oral or parenteral administration leading to high central nervous system (CNS) penetration. Based on initial in vitro studies, several quinuclidine derivatives show activity in brain nerve ending preparations. A series of toxicity studies has established the LD50 dose of soman at 1 hr and 24 hours. Based on the most potent inhibitors of ChAT activity, we have selected a series of tertiary amines as adjuncts to atropine-oxime therapy to ascertain whether such combinations increase protection against soman.
- Research Organization:
- Temple Univ., Philadelphia, PA (United States). School of Medicine
- OSTI ID:
- 7036932
- Report Number(s):
- AD-B-097937/7/XAB; CNN: DAMD17-82-C-2183
- Country of Publication:
- United States
- Language:
- English
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