Novel piperidinium and pyridinium agents as water-soluble acetylcholinesterase inhibitors for the reversal of neuromuscular blockade.
A series of piperidinium and pyridinium agents containing a common structural fragment of 5,6-dimethoxybenzothiophene have been synthesised as water-soluble acetylcholinesterase inhibitors. Several compounds, for example 42 (AChE IC(50) 0.03 microM) have been found to reverse the neuromuscular blockade induced by vecuronium bromide in vitro and in vivo. Coupled with their high water solubility (up to 30-60 mg/mL), these compounds are potentially useful as intravenous reversal agents of neuromuscular blocking agents in surgical anaesthesia.
Department of Medicinal Chemistry, Organon Laboratories Ltd., Newhouse, Lanarkshire ML1 5SH, UK. r.palin@organon.nhe.akzonobel.nl
Ronald
R
Palin
John K
JK
Clark
Phill
P
Cowley
Alan W
AW
Muir
Eleanor
E
Pow
Alan B
AB
Prosser
Robert
R
Taylor
Ming-Qiang
MQ
Zhang
D000110:Acetylcholinesterase / Q000187:drug effects*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D003964:Diaphragm / Q000187:drug effects; D003473:Neuromuscular Nondepolarizing Agents / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D014673:Vecuronium Bromide / Q000037:antagonists & inhibitors*; D014867:Water
D002800:Cholinesterase Inhibitors; D003473:Neuromuscular Nondepolarizing Agents; D010880:Piperidines; D011725:Pyridines; D014867:Water; D014673:Vecuronium Bromide; D000110:Acetylcholinesterase