Bispyridinium Compounds Inhibit Both Muscle and Neuronal Nicotinic Acetylcholine Receptors in Human Cell Lines.
Standard treatment of poisoning by organophosphorus anticholinesterases uses atropine to reduce the muscarinic effects of acetylcholine accumulation and oximes to reactivate acetylcholinesterase (the effectiveness of which depends on the specific anticholinesterase), but does not directly address the nicotinic effects of poisoning. Bispyridinium molecules which act as noncompetitive antagonists at nicotinic acetylcholine receptors have been identified as promising compounds and one has been shown to improve survival following organophosphorus poisoning in guinea-pigs. Here, we have investigated the structural requirements for antagonism and compared inhibitory potency of these compounds at muscle and neuronal nicotinic receptors and acetylcholinesterase. A series of compounds was synthesised, in which the length of the polymethylene linker between the two pyridinium moieties was increased sequentially from one to ten carbon atoms. Their effects on nicotinic receptor-mediated calcium responses were tested in muscle-derived (CN21) and neuronal (SH-SY5Y) cells. Their ability to inhibit acetylcholinesterase activity was tested using human erythrocyte ghosts. In both cell lines, the nicotinic response was inhibited in a dose-dependent manner and the inhibitory potency of the compounds increased with greater linker length between the two pyridinium moieties, as did their inhibitory potency for human acetylcholinesterase activity in vitro. These results demonstrate that bispyridinium compounds inhibit both neuronal and muscle nicotinic receptors and that their potency depends on the length of the hydrocarbon chain linking the two pyridinium moieties. Knowledge of structure-activity relationships will aid the optimisation of molecular structures for therapeutic use against the nicotinic effects of organophosphorus poisoning.
Norwegian Defence Research Establishment, Kjeller, Norway.
Avi
A
Ring
Norwegian Defence Research Establishment, Kjeller, Norway.
Bjorn Oddvar
BO
Strom
Dstl Porton Down, Salisbury, Wiltshire, United Kingdom; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom.
Simon R
SR
Turner
Dstl Porton Down, Salisbury, Wiltshire, United Kingdom.
Christopher M
CM
Timperley
Dstl Porton Down, Salisbury, Wiltshire, United Kingdom.
Michael
M
Bird
Dstl Porton Down, Salisbury, Wiltshire, United Kingdom.
A Christopher
AC
Green
Institute for Life Sciences, University of Southampton, Southampton, United Kingdom.
John E
JE
Chad
Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
Franz
F
Worek
Dstl Porton Down, Salisbury, Wiltshire, United Kingdom.
John E H
JE
Tattersall
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D006168:Guinea Pigs; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D062025:Organophosphate Poisoning / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D011726:Pyridinium Compounds / Q000633:toxicity*; D011978:Receptors, Nicotinic / Q000378:metabolism*
D009943:Organophosphorus Compounds; D011726:Pyridinium Compounds; D011978:Receptors, Nicotinic; D000110:Acetylcholinesterase