Neuromuscular blocking activities of some steroidal mono and bis-quaternary ammonium compounds with special reference to NN'-dimethylconessine.

The pharmacological properties of conessine, 3-/3-dimethylamino-con-5-ene, a steroidal alkaloid obtained from the bark and seeds of Holarrhena antidysenterica have been described (Burn, 1914; Stephenson, 1948). Quaternary salts of the alkaloid have been prepared (Polstorff & Schirmer, 1886; Bertho, 1944) but do not seem to have been examined pharmacologically. We report here the results of an investigation of structure-activity relationships in a series of quaternary ammonium compounds derived from conessine or related steroids which possess neuromuscular blocking properties of the non-depolarizing type. The results for one compound, NN'-dimethylconessine, which is typical of this group and has been submitted for clinical trial, are recorded in detail. supramaximal strength and 0.5 msec duration were applied directly to the tibialis anterior muscle between the tendon and the drill in the femur, using shielded silver wire. Close-arterial injections were made to the tibialis anterior muscle as described by Brown (1938). Gross muscle action-potentials were recorded on a Tektronix 502 dual-beam oscilloscope from platinum electrodes inserted through the belly and tendon of the tibialis muscle, and the antidromic nerve action potentials were recorded from shielded platinum electrodes placed on the sciatic nerve. Drugs were injected into the right external jugular vein through a tap cannula, and the left carotid arterial pressure was recorded using a mercury manometer. Artificial respiration was applied through-a. tracheal cannula connected to a Palmer respiration pump. of the muscle and potentiated the response induced by acetylcholine, they were assayed instead on the isolated semispinalis muscle of the chick (Child & Zaimis, 1960). Concentrations greater than 0.5 sg/ml. were assayable.