Non-depolarizing Neuromuscular Blocking Activity of Bisquaternary Amino Di- and Tripeptide Derivatives

Abstract

Herein we describe the synthesis of novel di- and tripeptide derivatives with two quaternary nitrogen groups attached and the biological testing of these compounds for neuromuscular blocking (NMB) activity in vitro and in vivo. 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 with an injectable formulation. From a small series of compounds 20c,e are identified as effective non-depolarizing NMB agents in vitro and in vivo in anesthetized cats and Rhesus monkeys with potencies similar to those of the clinical reference compounds rocuronium (4) and suxamethonium (2) (monkey ED(90) = 0.68, 0.23, 0.16, 5.04 micromol/kg, respectively). These new peptide derivatives 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 conclusion that the di- or tripeptide fragment can be regarded as an alternative template to the steroid or aliphatic ester of previously reported NMBs and within this tripeptide-derived series clog P correlates well with in vitro NMB activity.

Development of ultra short‐acting muscle relaxant agents: History, research strategies, and challenges

“…These observations, at least indirectly, may influence decision making in the design of new agents. Recent studies confirmed the direct correlation between NMB potency and lipophilicity, based either on indirect measurements of C log P values with NMB bisquaternary di-and tripeptides 24 or on lipophilic surface area calculations with bis quetarnery tropinyl diesters. 19 However, a clear correlation between lipophilicity and onset of action has not been shown in these studies.…”

“…Several formulas were developed for this purpose, 21,22 but their value has not yet been verified in series of new NMB agents. The significance of utilizing calculations of lipophylicity is underlined by experimental evidences showing direct correlation between potency and lipophilicity and reversed correlation between onset of action and lipophilicity in a series of amino-steroid 23 and peptide type 24 new NMB agents.…”

Recent Advances in Neuromuscular Blocking Agents

“…(7). Researchers at Organon Laboratories investigated whether compounds with a short peptide fragment between two ammonium cation heads could serve as non-depolarizing NMBs and explored the structure-activity relationship of such a series [59]. A peptide scaffold could confer a number of desirable properties including rapid in vivo degradation to nontoxic metabolits, low propensity to cross the blood-brain barrier, and straightforward synthesis from inexpensive starting materials.…”

“…Structures, in vitro Activity and Calculated Lipophilicity (clogP) of Bisquaternary Dipeptide Derivatives Measured in Chick Biventer[59] …”

Design of controlled releasing system: Synthesis of an amphiphilic copolymer endowed with acid‐labile side chains based on quaternarization of amine‐containing prepolymer with benzyl halide having acetal moiety

“…Another highly reliable approach to synthesis of polymers having quaternary ammonium salt is the treatment of precursor polymers having tertiary amino side chains with alkyl halides, by which their quaternarization are usually achieved under mild conditions with high efficiencies 8–13. So far, simple alkyl halides having long alkyl chains and those having simple functional groups have been used for controlling the hydrophilicity of the polymers that are critical parameter for their self‐association behaviors.…”