NEUROMUSCULAR BLOCKING ACTIVITY OF CYCLIC AND ACYCLIC BIS-QUATERNARY AMMONIUM ANALOGS OF MIVACURIUM CHLORIDE IN THE CAT

The purpose of this work was to identify a new ultra-short-acting neur omuscular blocking agent devoid of the potential to produce cardiovasc ular effects at greater than or equal to ED95 doses. Four new bis-quat ernary mivacurium analogues that are acyclic with respect to the bis-i soquinolinium nuclei and seven new bis-quaternary mivacurium analogues that are derivatives of (E)-oct-4-enedioic acid, (E)-oct-2-enedioic a cid, and (E)-oct-4-enedithioic acid, were synthesised and tested for n euromuscular blocking activity in the cat. In general, compared with m ivacurium, the acyclic analogues were of much lower potency but showed a faster onset (time from injection to maximum neuromuscular block) a nd a much shorter duration of action (time from injection to 95% recov ery) at approximately ED95 doses. However, these acyclic analogues had a considerably narrower safety margin (i.e., the ratio of doses that produce unwanted cardiovascular or autonomic effects to those that pro duce neuromuscular block) than mivacurium. The (E)-oct-4-enedioate and (E)-oct-4-enedithioate analogues showed a neuromuscular blocking prof ile similar to the acyclic analogues. The (E)-oct-2-enedioate isomer o f mivacurium did not have any advantageous neuromuscular blocking prop erties over mivacurium and, in fact, elicited cardiovascular and auton omic effects at much lower multiples of ED,,. Structural changes to mi vacurium, however minor, to either the inter-onium chain or the onium centres (or both) result in compounds whose cardiovascular and autonom ic safety profiles are highly compromised in return for the desirable rapid onset and brevity of neuromuscular blocking action at greater th an or equal to ED95 doses. The intact isoquinolinium nucleus appears t o confer a superior safety profile over that of an acyclic onium nucle us. (C) 1997 Elsevier Science B.V.