NEUROMUSCULAR BLOCKING N,N'-POLYMETHYLENE BISTROPANIUM, BIS 3-ALPHA-HYDROXYTROPANIUM AND BIS 3-OXOTROPANIUM COMPOUNDS

To explore the role of ester groups in the neuromuscular blocking (NMB ) property of various quaternary ammonium tropinesters, we have synthe sized and pharmacologically evaluated twenty bisquaternary ammonium de rivatives where two tropane (I), 3 alpha-hydroxytropane (II), or 3-oxo tropane (III) moieties were connected on their nitrogen atoms with a p olymethylene chain of C3-C12 length. The rank order of potency of thes e agents in the rat (evoked EMG responses of the ant. tibial muscle) w as: I, II, and III. Most potent were the longer chain (e.g. C10-C12) c ompounds of series I, yet they were inferior to bisquaternary ammonium tropinester derivatives (e.g. N,N'-polymethylene bisquaternary tropin esters, or bisquaternary derivatives of dicarboxylic acid tropinesters ). Although some of the agents (series I and II) showed a rapid onset and short duration of action-profile, they also exhibited cardiovascul ar side effects (e.g. cardiac vagal block and blood pressure changes). In the design of new NMB agents of rapid onset and short duration of action the presence of different ester groups in addition to an azabic yclo ring system (e.g. tropane), seems to be essential. (C) 1998 Elsev ier Science Inc.