James C. Wisowaty

Neuromuscular blocking activity of bis-4-benzyltetrahydroisoquinolinium esters in the cat

Abstract The purpose of this work was to identify a new ultra-short-acting neuromuscular blocking agent devoid of the potential to produce histamine-like cardiovascular effects at ≥ED 95 doses. Eight new bis -4-benzyltetrahydroisoquinolinium esters, derivatives of ( E )-oct-4-ene-1,8-dioyl acid, were tested for neuromuscular blocking activity in the cat and compared with mivacurium chloride. All compounds were more than ten times less potent than mivacurium but exhibited a rapid onset of action (≊0.9–1.8 min from injection to maximum neuromuscular block) and an ultra-short duration of neuromuscular block (≊5–8 min from injection to 95% recovery) at approximately ED 95 doses; however, at these and even lesser doses, they also produced histamine-like cardiovascular effects and inhibited the response to vagal stimulation. The data suggest that, in the benzyltetrahydroisoquinolinium class of neuromuscular blocking agents, 4-benzyl substitution may offer the desired rapid onset and ultra-short duration of action at ED 95 doses, but these advantages are offset by the adverse cardiovascular and autonomic effects which occur at ≤ED 95 doses.

Neuromuscular blocking activity of cyclic and acyclic bis-quaternary ammonium analogues of mivacurium chloride in the cat

Abstract 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.