Structure-activity relationships: from tubocurarine to the present day

Abstract

Many of the structural features of neuromuscular blocking agents that determine activity at the cholinergic nicotinic receptor at the motor endplate were established by the 1960s. The important features were: The presence of two ammonium groups, one of which should be quaternary. The incorporation of the nitrogen atom of these amine groups into an aromatic ring structure. An optimum interonium distance, within certain limits, of 1.4 nm. The presence of either ester groups in the interonium linkage to encourage enzymatic breakdown, or structural features that ensure rapid plasma clearance, to limit duration of action. More recent work has focused upon two particular series of bisquaternary compounds, the bisbenzylisoquinolinium diesters and the 2,16-androstane derivatives, which are relatively free of unwanted cardiovascular sideeffects. Modification of these compounds has given us clinically useful intermediate and long-acting agents. Mivacurium looks promising as a short-acting agent. However, we still do not have an ultrashort-acting non-depolarizing agent with as rapid an onset as suxamethonium, and theoretical considerations suggest that this may be a difficult goal. New approaches with alternative compounds provide reason for optimism that this ideal may yet be achieved.