Synthesis and structure-toxicity relationships of three new stable analogues of acetyl-seco-hemicholinium-3

Abstract

In order to develop and study inhibitors of neuromuscular function which act presynaptically, 3 stable analogues of acetyl-seco-hemicholinium-3 (AcHC-3,2) were prepared. These analogues have 2-ethoxyethyltrimethylammonium, 4-oxopentyltrimethylammonium and n-pentyltrimethylammonium moieties substituted for the 2-acetylethyltrimethylammonium (acetylcholine) moieties of AcHC-3 (2) to form the ether 3, ketone 4, and alkane 5 analogues of AcHC-3 (2). Although AcHc-3 (2) deesterifies rapidly in basic solutions and slowly at pH 7.4, it is stable in H2O or D2O under slightly acidic conditions. All of the analogues are stable for extended time under both slightly acidic conditions and at pH 7.4 in H2O or D2O. 2 reacts with acetylcholinesterase and butyrylcholinesterase within seconds in H2O at pH 7.4. However, deesterification of 2 with subsequent cyclization to the hemiacetal form of hemicholinium-3 (HC-3,1) is prevented at pH 7.4., possibly by an irreversible binding of 2 to the enzyme. The analogues 3-5, however, do not react under identical conditions. Mouse toxicity studies (LD50) indicate that 2 is approximately as toxic as HC-3 (1); 3, 4 and 5 are 14.2, 23.8 and 43.1 times less toxic, respectively. The toxic effects of 3-5, like 1 and 2, are antagonized by choline but not by neostigmine in mice. Structure-activity relationships of 1-5 are discussed.