THE EFFECTS OF STRUCTURAL VARIATION IN THE QUATERNARY NITROGEN CENTERS OF BENZOQUINONIUM CHLORIDE UPON NEUROMUSCULAR BLOCKING ACTIVITY

¹ Pharmacology Section, Sterling-Winthrop Research Institute, Rensselaer, New York

The effects of sequential substitution in the quaternary nitrogen centers of benzoquinonium

3. The all-ethyl derivative resembled d-tubocurarine as follows: (a) no obvious muscle stimulation, (b) effective reversal by edrophonium and neostigmine in the cat, dog, rabbit and mouse, (c) flaccid paralysis in the pigeon and (d) low potency variation among species.

4. The all-methyl derivative resembled decamethonium as follows: (a) produced intense generalized fasciculation in the cat, (b) its effects were potentiated by edrophonium and neostigmine in the cat, antagonized in the dog and antagonized by neostigmine in the mouse and (c) demonstrated a relatively high potency variation among species.

5. The anticholinesterase activity of benzoquinonium, amounting to 25 per cent of that of neostigmine, was associated with the presence of the benzyl group in the quaternary nitrogen centers. Replacement by an alkyl group or appropriate substitution within the benzyl group caused a reduction in anticholinesterase activity which, when less than two per cent of that of neostigmine, was associated with antagonism by edrophonium and neostigmine.

6. The mouse, pre-treated with neostigmine, was found to be sensitive to the presence of anticholinesterase activity in compounds which produce neuromuscular blockade. When anticholinesterase activity was increased to 10 per cent of that of neostigmine, antagonism was replaced by potentiation which increased in intensity as anticholinesterase activity was increased to 25 per cent but showed no further increase when the anticholinesterase activity was increased to 210 per cent of that of neostigmine.

7. Neostigmine and edrophonium were equi-potent in causing antagonism of the effects of d-tubocurarine in the mouse. Although a substantially larger dose of edrophonium was required, both neostigmine and edrophonium also caused antagonism of the effects of decamethonium in the mouse.

8. Both neostigmine and edrophonium produced potentiation of the effects of benzoquinonium in the mouse. Neostigmine, however, was approximately a thousand times as potent as edrophonium in demonstrating this effect on benzoquinonium.

9. Failure to observe reversal of the effects of benzoquinonium by neostigmine and edrophonium was discussed. The data indicate that this failure is attributable to the inherent anticholinesterase activity of benzoquinonium chloride.

10. The importance of estimation of the specificity of neuromuscular blocking activity, particularly when working with d-tubocurarine-like compounds, was iscussed.

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