Non-depolarizing neuromuscular blocking activity of bisquaternary amino di- and tripeptide derivatives

Herein we describe the synthesis of novel di- and tripeptide derivatives wi th two quaternary nitrogen groups attached and the biological testing of th ese compounds for neuromuscular blocking (NMB) activity in vitro and in viv o. The short peptide scaffold was selected because it offers potential for desired distance between the two pharmacophoric quaternary nitrogen groups, short duration of action, straightforward synthesis, and compatibility wit h an injectable formulation. From a small series of compounds 20c,e are ide ntified as effective non-depolarizing NMB agents in vitro and in vivo in an esthetized cats and Rhesus monkeys with potencies similar to those of the c linical reference compounds rocuronium (4) and suxamethonium (2) (monkey ED 90 = 0.68, 0.23, 0.16, 5.04 mu mol/kg, respectively). These new peptide der ivatives 20c,e have similar potency and onset time but longer duration and slower recovery than the clinically used reference compounds. The structure -activity relationships described for this chemical series lead to the conc lusion that the di- or tripeptide fragment can be regarded as an alternativ e template to the steroid or aliphatic ester of previously reported NMBs an d within this tripeptide-derived series clog P correlates well with in vitr o NMB activity.