Stereochemical Preferences for Curarimimetic Neuromuscular Junction Blockade II: Enantiomeric Bisquaternary Amines as Probes

Abstract

Two pairs of bisquaternary enantiomeric neuromuscular junction blocking agents as well as their diastereomeric meso forms were prepared in which the carbon asymmetry is adjacent to the quaternary center. The tertiary amines from which the blocking species were obtained by methyl iodide treatment were N‐methylpavine and 1,1′‐dodecamethylenebis(6,7‐dimethoxy‐2‐methyl‐1,2,3,4‐tetrahydroisoquinoline). Blocking potencies were determined by the mouse inclined screen assay and by the cat tongue‐hypoglossal nerve technique. The mouse assay showed no statistical difference between the enantiomeric probes derived from N‐methylpavine and only a modest superiority of the (R‐R) isomer over the (S‐S) isomer in the case of the tetrahydroisoquinoline compounds. The cat assay showed a modest statistically significant (R‐R) > (S‐S) difference in potencies in both kinds of probes. The diastereomeric meso‐compounds were less active than the enantiomers in mice but were of intermediate activity in the cat determination. Acetylcholinesterase‐inhibiting activity was determined for each probe to discount potency differences from this source, and no significant differences in blocking potency attributable to preferential enzyme inhibition by the probes were noted.