Rational Elements in the Development of Superior Neuromuscular Blocking Agents

Martin‐Smith, M.

doi:10.1016/b978-0-12-060302-2.50019-1

Cited by 15 publications

(11 citation statements)

References 451 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…suxamethonium (2), and the non-depolarizing agents, e.g. pancuronium (3), rocuronium (4), and atracurium (5). The nondepolarizing agents act as competitive antagonists for acetylcholine, and their action may be reversed by an anticholinesterase agent, e.g.…”

Section: Introductionmentioning

confidence: 99%

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

Booij¹,

Broek²,

Caulfield³

et al. 2000

J. Med. Chem.

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Booij¹,

Broek²,

Caulfield³

et al. 2000

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…The structure-activity relationships noted among diquaternary steroidal drugs are of interest, and deserve brief mention. For more extensive reviews, see BUCKETT ( 1972) and MARTIN-SMITH (1971). The internitrogen distance of most steroidal neuromuscular blocking agents is approximately 9-1 1 Angstroms (MAR- TIN-SMITH 197 1, BUCKETT 1972).…”

Section: Clinical Effectsmentioning

confidence: 99%

The Quest for a Short‐Acting Nondepolarizing Neuromuscular Blocking Agent

Savarese

Kitz

1974

Acta Anaesthesiol Scand

View full text Add to dashboard Cite

show abstract

“…John J. Lewis, well remembered as the author of Lewis's Pharmacology, died tragically the following year. Martin-Smith considered that within certain limits interonium distance per se was relatively unimportant in determining neuromuscular blocking activity, while other factors such as the number of weak bonding contacts possible between the postjunctional membrane and the molecular units separating theonium centres of the bisquaternary ammonium compound could be influential [19]. Martin-Smith and Lewis gave advice to the Organon team in Scotland, which included Colin L. Hewett (director of research), W. Roger Buckett (head of pharmacology) and David S. Savage (medicinal chemist) [20].…”

mentioning

confidence: 99%

Prelude to pancuronium and vecuronium

McKenzie

2000

Anaesthesia

View full text Add to dashboard Cite

SummaryThe discovery of the neuromuscular blocking activity of malouetine isolated from Malouetia bequaertiana Woodson by Quevauviller and Laine Â in 1960 stimulated interest in aminosteroids as potential neuromuscular blockers. Alauddin (a pharmacist) and Martin-Smith (a medicinal chemist) began research in this area, which was then taken up by pharmaceutical companies. Pure pancuronium was synthesised in 1964 by Savage and his co-workers, directed by Hewett. Pharmacologists headed by Buckett discovered that pancuronium was far more potent than dtubocurarine and had minimal side-effects. Buckett quickly recognised the value of pancuronium, and his persistence resulted in successful clinical trials, followed by the commercial launch of pancuronium in 1968. Vecuronium was synthesised, tested and the studies published by Buckett, Hewett and Savage in 1973, but this was before anaesthetists called for a`clean muscle relaxant' and, furthermore, it was unstable in aqueous solution. Hence, it was only promoted for clinical trials six years later.

show abstract

Rational Elements in the Development of Superior Neuromuscular Blocking Agents

Cited by 15 publications

References 451 publications

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

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

The Quest for a Short‐Acting Nondepolarizing Neuromuscular Blocking Agent

Prelude to pancuronium and vecuronium

Contact Info

Product

Resources

About