A series o
f potent neuronal nicotinic acetylcholine receptor (nAChR) ligands based on a 3,8-diazabicyclo[4.2.0]octane core have been synthesized and evaluated
for a
ffinity and agonist e
fficacy at the human higha
ffinity nicotine recognition site (h
fchars/alpha.gi
f" BORDER=0>4
fchars/beta2.gi
f" BORDER=0 ALIGN="middle">2) and in a rat model o
f persistent nociceptive pain (
formalin model).Numerous analogs in this series exhibit picomolar a
ffinity in radioligand binding assays and nanomolaragonist potency in
functional assays, placing them among the most potent nAChR ligands known
for theh
fchars/alpha.gi
f" BORDER=0>4
fchars/beta2.gi
f" BORDER=0 ALIGN="middle">2 receptor. Several o
f the compounds reported in this study (i.e.,
24,
25,
28,
30,
32, and
47) exhibitequivalent or greater a
ffinity
for the h
fchars/alpha.gi
f" BORDER=0>4
fchars/beta2.gi
f" BORDER=0 ALIGN="middle">2 receptor relative to epibatidine, and like epibatidine, manyexhibit robust analgesic e
fficacy in the rat
formalin model o
f persistent pain.