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The purpose of this work was to identify a new ultra-short-acting neuromuscular blocking agent devoid of the potential to produce cardiovascular effects at ≥ED 9 5 doses. Four new bis -quaternary mivacurium analogues that are acyclic with respect to the bis -isoquinolinium nuclei and seven new bis -quaternary mivacurium analogues that are derivatives of ( E )-oct-4-enedioic acid, ( E )-oct-2-enedioic acid, and ( E )-oct-4-enedithioic acid, were synthesised and tested for neuromuscular blocking activity in the cat. In general, compared with mivacurium, the acyclic analogues were of much lower potency but showed a faster onset (time from injection to maximum neuromuscular block) and a much shorter duration of action (time from injection to 95% recovery) at approximately ED 9 5 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 produce neuromuscular block) than mivacurium. The ( E )-oct-4-enedioate and ( E )-oct-4-enedithioate analogues showed a neuromuscular blocking profile similar to the acyclic analogues. The ( E )-oct-2-enedioate isomer of mivacurium did not have any advantageous neuromuscular blocking properties over mivacurium and, in fact, elicited cardiovascular and autonomic effects at much lower multiples of ED 95 . Structural changes to mivacurium, however minor, to either the inter-onium chain or the onium centres (or both) result in compounds whose cardiovascular and autonomic safety profiles are highly compromised in return for the desirable rapid onset and brevity of neuromuscular blocking action at ≥ED 95 doses. The intact isoquinolinium nucleus appears to confer a superior safety profile over that of an acyclic onium nucleus. |
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