Abstract
The role of specific nicotinic receptor (nAChR) subtypes in antinociception has not
been fully elucidated because of the lack, until recently, of selective tool compounds.
(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiopene-2-carboxamide) (compound B) is reported to be an agonist selective
for the α7nAChR and in the present study was found to be efficacious in inflammatory pain models
in 2 species. Compound B reversed complete Freund adjuvant–induced reductions in paw
withdrawal thresholds in rat and mouse in a dose-related manner, producing maximum
reversals of 65% ± 4% at 10 mg/kg and 87% ± 15% at 20 mg/kg. When rats and mice were
predosed with the centrally penetrant, broad-spectrum nicotinic receptor antagonist
mecamylamine, the efficacy of the agonist was significantly inhibited, producing reversals
of only 11% ± 5% at 10 mg/kg and 5% ± 13% at 20 mg/kg, confirming activity via nicotinic
receptors. Rats were also predosed systemically with the selective low-brain penetrant
α7-antagonist methyllycaconitine, which had no effect on agonist activity (90% ± 18%
at 10 mg/kg), suggesting a central involvement. This hypothesis was further established
with methyllycaconitine completely inhibited the agonist effect when dosed intrathecally
(1% ± 7%).
Perspective
These studies provide good rationale for the utility of selective, central nervous
system penetrant agonists at the α7-nicotinic receptor for the treatment of inflammatory pain.
Key words
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Article info
Publication history
Published online: April 18, 2008
Accepted:
January 19,
2008
Received in revised form:
January 8,
2008
Received:
June 21,
2007
Footnotes
Supported by GlaxoSmithKline.
International Patent Application Publication No. WO01/60821A1 (AstraZeneca AB) Phillips E, Schmiesing R (August 23, 2001). Novel biarylcarboxamides.
Identification
Copyright
© 2008 American Pain Society. Published by Elsevier Inc. All rights reserved.
