B. Badio et al.rEuropean Journal of Pharmacology 321 (1997) 189–194
193
4
. Discussion
1995.. ABT 8295, the R-Žy.-enantiomer of ABT 418,
was stated to be 2-fold less active than ABT 418 ŽHolladay
et al., 1995.. Both in vitro and in vivo, the effects of
Ž".-epiboxidine were blocked by nicotinic antagonists
Žsee Section 3. as was previously reported for the epiba-
tidines ŽBadio and Daly, 1994..
Ž".-Epiboxidine proved to be a potent nicotinic recep-
tor agonist, particularly at the ganglionic-type receptor of
PC12 cells, where it was not significantly less potent than
Žy.-epibatidine ŽTable 1.. Activity at the neuromuscular-
type receptor of TE671 cells and affinity versus nicotinic-
binding to neuronal-type receptors in brain membranes
was, in contrast, markedly reduced by replacement of the
chloropyridinyl moiety in epibatidine with the methylisox-
azolyl moiety in epiboxidine. Replacement of the pyridinyl
moiety of Žy.-nicotine ŽS-enantiomer., with the meth-
ylisoxazolyl moiety in ABT 418 ŽS-enantiomer., resulted
in about a 2-fold reduction in activity at both the gan-
glionic-type receptor and the neuromuscular-type receptor,
while a 10-fold reduction occurred for the central neu-
ronal-type receptor ŽTable 1.. Thus, it appears that the
nortropane ring of epiboxidine and epibatidine is the pri-
mary determinant of high nicotinic activity, while substitu-
tion of the pyridinyl moiety in either nicotine or epibati-
dine by a methylisoxazolyl moiety markedly decreases
affinityrpotency at central neuronal-type receptors. In the
case of epibatidine the replacement of the pyridinyl moiety
with a methylisoxazolyl moiety also markedly reduces
potency at the neuromuscular-type receptors.
In summary, Ž".-epiboxidine represents a potent
antinociceptive agent with a better activityrtoxicity ratio
than epibatidine, the natural alkaloid that served as a
molecular model. Tentatively, it might be concluded that
central a b nicotinic receptors are primarily involved in
4
2
the antinociceptive activity of Žy.-epibatidine, since a
10-fold reduction of affinity of Ž".-epiboxidine at such
receptors compared to Žy.-epibatidine seems paralleled by
about a 10-fold reduction in antinociceptive activity of
Ž".-epiboxidine compared to Žy.-epibatidine. Ganglionic
receptors seem less likely to be involved since Ž".-epi-
boxidine is not significantly less potent than Žy.-epibati-
dine at such receptors. Ž".-Epiboxidine provides a novel
new agonist for investigation of the receptor subtypes
involved in the central pharmacological activities of nico-
tine.
Acknowledgements
The altered profile of selectivity of Ž".-epiboxidine
The authors are grateful to Dr. M. Damaj ŽMedical
College of Virginia, Richmond, VA, USA. for a sample of
ABT 418.
and ABT 418 for nicotinic receptor subtypes would be
expected to change the in vivo profile of pharmacologic
and toxicologic activity. Ž".-Epiboxidine was about 10-
fold less potent than Žy.-epibatidine as an antinociceptive
agent ŽFig. 3., but appeared about 20-fold less toxic in a
comparison with Žy.-epibatidine Žsee Section 3.. Compar-
isons of in vivo effects of ABT 418 and Žy.-nicotine have
been previously reported ŽBriggs et al., 1995; Brioni et al.,
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