piperidines and asoxime-chloride

In experiments on male rats, the effect of selected cholinolytic agents (atropine, benactyzine, G 3063) in combination with the reactivator of cholinesterases HI-6 on the cholinergic and non-cholinergic effects of GV substance in the course of acute sublethal intoxication was compared. The cholinergic affects of GV substance were examined by means of the changes in the activity of cholinesterases in whole blood, the CNS, diaphragm and liver, the noncholinergic stressogenic effects by means of the changes in the level of corticosterone in plasma and the activity of tyrosine amino transferase in the liver. It follows from the changes in the activity of cholinesterases that the cholinergic effects of GV substance are least influenced by atropine, whereas benactyzine and G 3063 exert an approximately similar effect. The difference in the effect is evident especially in the 24th hour of intoxication. Similarly stressogenic effects of GV substance are least influenced by an antidotal combination of atropine and HI-6. It means that the centrally acting cholinolytic agents benactyzine and G 3063 are more advantageous for the therapy of GV substance poisonings than the peripherally acting atropine.

Topics: Acute Disease; Animals; Atropine; Benactyzine; Cholinergic Antagonists; Cholinesterase Reactivators; Cholinesterases; Male; Organophosphorus Compounds; Oximes; Piperidines; Poisoning; Pyridinium Compounds; Rats; Rats, Wistar; Tyrosine Transaminase

The mode of interaction of bisquaternary pyridinium oximes with rat brain muscarinic receptors in cerebral cortex and brain stem preparations was studied by the use of the tritium-labeled antagonist N-methyl-4-piperidyl benzilate ( [3H] 4NMPB). Binding of the labeled muscarinic antagonist was inhibited by these drugs, the most potent inhibitors being 1-(2-hydroxyiminoethylpyridinium)-1-(3-cyclohexylcarboxypyridin ium)dimethyl-ether (HGG-42) and its 3-phenylcarboxypyridinium analog (HGG-12) (apparent KI = 1.3-1.7 and 1.8-2.2 microM, respectively). Analysis of the binding properties suggested that binding of the muscarinic antagonist and the bisquaternary pyridinium oximes was nonexclusive. Kinetic binding data provide evidence that the drugs inhibit binding of muscarinic antagonists in an allosteric manner, with a resulting decrease in the rates of both association of [3H]4NMPB to the receptor and its dissociation from it. These effects were observed both in brain stem and in cortical preparations even after pretreatment and washing out of the inhibitors. The selective natures of HGG-12 and HGG-42 were apparent from their irreversible effects on the number of muscarinic binding sites. In brain stem, the presence of these drugs resulted in a loss of about 30% of binding sites, which accounts in part for the apparent decrease in maximal binding capacity observed in the equilibrium binding of [3H]4NMPB. In the cortex, however, only approximately 10% of the muscarinic receptors were lost upon exposure to these drugs. The decrease in the muscarinic receptor population of the brain stem was dependent on both concentration and time and occurred both in vitro and in vivo following injection of HGG-12 into rats. Unlike the in vitro loss of receptor sites, which was irreversible, the in vivo effect was restored 2 hr after the injection. Taken together, the results suggest that the bisquaternary oximes are allosteric inhibitors of the muscarinic acetylcholine receptor and may be capable of distinguishing between receptor states and inducing specific irreversible effects. Because of these properties, the drugs may prove extremely useful as sensitive probes in studies on the nature of the agonist-receptor-effector relationship.

Topics: Animals; Benzilates; Brain; Dose-Response Relationship, Drug; Kinetics; Mathematics; Obidoxime Chloride; Oximes; Piperidines; Pyridinium Compounds; Rats; Receptors, Muscarinic

The role of the functional substituents on the pyridinium ring of bisquaternary pyridinium compounds, mostly oximes, in exerting reversible and irreversible inhibition of binding of [3H]-N-methyl-4-piperidyl benzilate [( 3H]-4NMPB) to rat brain stem muscarinic receptors was studied. The drugs tested, i.e. HGG-42, HGG-12, HGG-52, HI-6, obidoxim, SAD-128 and TMB-4, could reversibly inhibit binding of [3H]-4NMPB, with the highest potency (KI = 1.7 - 6 microM) exhibited by analogs possessing hydrophobic substituents at position 3 or 4 of the pyridinium ring. Bisquaternary drugs possessing an oxime moiety at position 2, but not at position 4 of the pyridinium ring, could also induce about 30% reduction of maximal binding capacity (Bmax) (loss of muscarinic receptors) in addition to their reversible effect. Thus the structural correlates of the reversible and the irreversible effects of these drugs are different.

Topics: Animals; Benzilates; Binding, Competitive; Brain Stem; Cell-Free System; Obidoxime Chloride; Oximes; Parasympatholytics; Piperidines; Pyridinium Compounds; Rats; Receptors, Muscarinic; Structure-Activity Relationship; Trimedoxime