Sterochemical preferences for curarimimetic neuromuscular junction blockade III: enantiomeric bisquaternary amines related to benzoquinonium as probes.
Enantiomeric neuromuscular junction blocking agents, which are of the benzoquinonium type but which have a methyl group introduced adjacent to the quaternary moieties to provide an asymmetric center were synthesized and tested to determine whether the neuromuscular junction exhibits the relatively modest (R) greater than (S) superiority shown toward previously tested bisquaternaries. Testing included a mouse inclined screen assay and an in vivo cat hypoglossal nerve-tongue preparation, as well as standard estimations of anticholinesterase activity since the candidate compounds are known to have such a component in their activity spectrum. The observed 2:1 difference in blocking activity favoring the compound with an (R)-configuration is the same as that for previously tested bisquaternaries, both in direction and magnitude. Furthermore, it cannot be accounted for by preferential inhibition of acetylcholinesterase by the (S)-enantiomer. Absolute configurations of the enantiomers were assigned on the basis of comparison with compounds of known configuration.
D000588:Amines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002384:Catalysis; D002415:Cats; D002800:Cholinesterase Inhibitors; D007002:Hypoglossal Nerve / Q000187:drug effects; D007536:Isomerism; D007928:Lethal Dose 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008968:Molecular Conformation; D003473:Neuromuscular Nondepolarizing Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D011809:Quinones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D014059:Tongue / Q000187:drug effects; D014403:Tubocurarine / Q000494:pharmacology
D000588:Amines; D002800:Cholinesterase Inhibitors; D003473:Neuromuscular Nondepolarizing Agents; D000644:Quaternary Ammonium Compounds; D011809:Quinones; C004991:benzoquinonium; D014403:Tubocurarine