Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors.
Development of analgesic agents for the treatment of severe pain requires the identification of compounds that are devoid of opioid receptor liabilities. A potent (inhibition constant = 37 picomolar) neuronal nicotinic acetylcholine receptor (nAChR) ligand called ABT-594 was developed that has antinociceptive properties equal in efficacy to those of morphine across a series of diverse animal models of acute thermal, persistent chemical, and neuropathic pain states. These effects were blocked by the nAChR antagonist mecamylamine. In contrast to morphine, repeated treatment with ABT-594 did not appear to elicit opioid-like withdrawal or physical dependence. Thus, ABT-594 may be an analgesic that lacks the problems associated with opioid analgesia.
Bannon
A W
AW
Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Decker
M W
MW
Holladay
M W
MW
Curzon
P
P
Donnelly-Roberts
D
D
Puttfarcken
P S
PS
Bitner
R S
RS
Diaz
A
A
Dickenson
A H
AH
Porsolt
R D
RD
Williams
M
M
Arneric
S P
SP
D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008024:Ligands; D008464:Mecamylamine / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology; D009412:Nerve Fibers / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009469:Neuromuscular Junction / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D011725:Pyridines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000209:etiology; D009435:Synaptic Transmission / Q000187:drug effects
C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; D018712:Analgesics, Non-Narcotic; D001384:Azetidines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D008464:Mecamylamine; D009538:Nicotine; D009020:Morphine; C082748:epibatidine; D002211:Capsaicin