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The present investigation was performed in order to clarify the mechanism of ataxic behavior following the administration of 2-(3-dimethylaminopropyl)-1, 3, 3a, 4, 9, 9a-hexahydro-4, 9-o-benzeno-2H-benz[f]isoindole dimethiodide (MI-65-S) to mammals. For several years, many bis-quaternary ammonium salts containing a bicyclo(2.2.2) octane ring in their large cationic head have been synthesized in this laboratory. Since almost all of these compounds have potent ganglionic blocking activity, at first pharmacological attention was mainly paid to their use as clinical hypotensive agents (1-4). Recently, one of a new series of derivatives, MI-65-S, was synthesized. In the present study it has been found that this compound has not only a relatively potent ganglionic blocking action, but also brings about a long-lasting ataxic behavior in mammals. Moreover, it has been shown that MI-65-S produces a remarkable decrease in the frequency of the muscle spindle discharges. As the muscle spindle plays an important role in the maintenance of skeletal muscle tone, depression of its activity by a chemical substance may be a possible mechanism for the production of ataxic behavior. At present there are very few compounds which are known to possess a depressant effect on the muscle spindle. Studies were also performed on seven derivatives which are similar to MI-65-S in chemical structures, and the relation between chemical structure and activity on the muscle spindle was also discussed at the end of this report.

japanese journal of pharmacology/japanese journal of pharmacology

PHARMACOLOGICAL PROPERTIES OF A BIS-QUATERNARY AMMONIUM SALT OF THE DIBENZO-BICYCLO(2.2.2) OCTANE SERIES, ESPECIALLY ITS DEPRESSANT EFFECT ON THE MUSCLE SPINDLE