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4
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Arendash, G.W., Sanberg, P.R., Sengstock, G.J., 1995a. Nicotine en-
1
990., and GTS-21 ŽArendash et al., 1995a,b. was ob-
hances the learning and memory of aged rats. Pharmacol. Biochem.
Behav. 52, 517–523.
Arendash, G.W., Sengstock, G.J., Sanberg, P.R., Kem, W.R., 1995b.
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tion of the nicotinic receptor agonist GTS-21. Brain Res. 674, 252–
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Arneric, S.P., Sullivan, J.P., Williams, M., 1995. Neuronal nicotinic
acetylcholine receptors—novel targets for CNS therapeutics. In:
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served and no decline in effectiveness in the delayed
matching-to-sample task was observed in primates treated
with ABT-418 ŽArneric et al., 1995.. No tolerance to the
memory effects of TC-1734 was observed following
chronic exposure ŽLippiello et al., 1998.. Similarly, no
tolerance to the analgesic effects of ABT-594 or TC-2403
was seen following chronic administration ŽBannon et al.,
998.. The lack of tolerance to CNS-mediated effects of
1
Generation of Progress. Raven Press, New York, pp. 1–16.
Bannon, A.W., Decker, M.W., Curzon, P., Buckley, M.J., Kim, D.J.B.,
Radek, R.J., Lynch, J.K., Wasicak, J.T., Lin, N.-H., Arnold, W.H.,
Holladay, M.W., Williams, M., Arneric, S.P., 1998. ABT-594 wŽR.–
TC-2559 reported in this work is consistent with previous
reports.
TC-2559 is neuroprotective in vitro. A number of stud-
ies have demonstrated a neuroprotective effect of nicotine
and nicotinic receptor ligands both in vitro and in vivo.
These include effects in in vitro models demonstrating
neuroprotective effects of nicotinic receptor ligands on
inhibition of neuronal death resulting from beta-amyloid
toxicity ŽSalomon et al., 1996; Kihara et al., 1998.,
NMDA-mediated cytotoxicity ŽAkaike et al., 1994; Marin
et al., 1994; Donnelly-Roberts et al., 1996; Kaneko et al.,
997., or growth factor deprivation ŽYamashita and Naka-
mura, 1996.. In vivo models demonstrating nicotine’s abil-
ity to rescue neurones from death resulting from surgically
induced nucleus basalis lesions in young and aged animals
ŽJanson et al., 1988; Janson and Moller, 1993; Sjak-Shie
and Meyer, 1993; Nanri et al., 1997., chemically induced
neurotoxicity in MPTP models ŽJanson et al, 1988. and
systemic kainic acid-induced excitotoxic effects ŽBorlon-
gan et al., 1995. have been reported. The neuroprotective
5
-Ž2-azetidinylmethoxy.-2-chloropyridinex: a novel, orally effective
antinociceptive agent acting via neuronal nicotinic acetylcholine re-
ceptors: II. In vivo characterization. J. Pharmacol. Exp. Ther. 285,
787–794.
Bencherif, M., Lovette, M.E., Fowler, K.W., Arrington, S., Reeves, L.,
Caldwell, W.S., Lippiello, P.M., 1996. RJR-2403: a nicotinic agonist
with CNS selectivity: I. In vitro characterization. J. Pharmacol. Exp.
Ther. 279, 1413–1421.
Bencherif, M., Caldwell, W.S., Gatto, G., Dull, G.M., Fowler, K.W.,
Lippiello, P.M., 1998a. TC-2559 is selective for CNS receptors and is
neuroprotective in vitro. 28th Annual Meetings of the Soc. for
Neurosci., Abstr.
1
Bencherif, M., Schmitt, J.D., Bhatti, B.S., Crooks, P., Caldwell, W.S.,
Lovette, E., Fowler, K.W., Reeves, L., Lippiello, P.M., 1998b. The
heterocyclic substituted pyridine derivative Žq.-2-Ž-3-pyridinyl.-1-
azabicyclo 2.3.4 octane RJR-2429 : a selective ligand at nicotinic
acetylcholine receptors. J. Pharmacol. Exp. Ther. 284, 886–894.
Borlongan, C.V., Shytle, R.D., Ross, S.D., Shimizu, T., Freeman, T.B.,
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2
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effects of nicotinic receptor ligands may provide additional
chronic benefit in conditions where cognitive enhancement
is sought.
Several recent reviews and study reports have presented
perspectives on how nicotinic acetylcholine receptor-
targeted compounds having some of the positive effects of
nicotine Že.g., anxiolysis, anti-depressant, cognitive en-
hancement, neuroprotection. with reduced side effects
might be developed. Thus, intense effort has been directed
toward the development of nicotinic agonists that are
potent and have selectivity for CNS nicotinic acetylcholine
receptor subtypes. The recent discovery of nicotinic recep-
tor ligands having selectivity for neuronal nicotinic acetyl-
choline receptors, such as TC-2403 and TC-2559, suggests
that the successful clinical development of potent nico-
tinic-based therapeutics is imminent and may expand the
therapeutic arsenal available for treatment of a variety of
CNS disorders.
Brioni, J.D., Decker, M.W., Sullivan, J.P., Arneric, S.P., 1997. The
pharmacology of Žy.-nicotine and novel cholinergic channel modula-
tors. In: August, J.T., Anders, M.W., Murad, F., Coyle, J.T. ŽEds..,
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1
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Reid, R., Sacaan, A.I., Santori, E., Stauderman, K.A., Whelan, K.,
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2
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Decker, M.W., Brioni, J.D., Sullivan, J.P., Buckley, M.J., Radek, R.J.,
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