made on the epibatidine skeleton in an effort to establish the
required parameters in terms of stereochemistry, N-N distance,
bioisosteric rings, level of conformational constraint, or azabi-
cyclic changes.5
Synthesis of Azabicyclo[2.2.n]alkane Systems
as Analogues of 3-[1-Methyl-2-(S)-pyrrolidinyl-
methoxy]pyridine (A-84543)
In this field, several 3-pyridyl ether compounds have been
synthesized at Abbott Laboratories and some of them showed
a subnanomolar affinity for central neuronal nicotinic acetyl-
choline receptors.6 Two of these compounds, A-85380 (1) and
A-84543 (2), have attractive features, and they have been the
subject of diverse syntheses.6 Moreover, a large number of
analogues have been obtained, particularly with substituents at
the different positions of the pyridine ring (Figure 1).7 On the
other hand, previous studies demonstrated the importance
7-azabicyclo[2.2.1]heptane system for molecular recognition of
epibatidine at nAChRs.8a With this proposal, analogues of
compounds 1 and 2 were synthesized8bsexo-3 and endo-3
stereoisomerssin which an ether linker has been incorporated
in the 2-position of the 7-azabicyclo[2.2.1]heptane system;
nevertheless they gave a poor responsespossibly due to the large
distance between nitrogen atoms (Figure 1).
J. Carreras, A. Avenoza,* J. H. Busto,* and J. M. Peregrina
Departamento de Qu´ımica, UniVersidad de La Rioja, Grupo de
S´ıntesis Qu´ımica de La Rioja, UA-CSIC, 26006 Logron˜o, Spain
ReceiVed January 12, 2007
In our previous work we developed the synthesis, investigated
the activity, and carried out a theoretical study of ABT-418
analogues 4 and 5 using the 1-substituted 7-azabicyclo[2.2.1]-
heptane as a core9 (Figure 1). Taking into account the
This work is connected with the epibatidine field and
describes the synthesis of several analogues of compounds
that present affinity for nicotinic acetylcholine receptors, such
as 3-[1-methyl-2-(S)-pyrrolidinylmethoxy]pyridine (A-84543).
These analogues bear a 3-pyridyl ether substituent at the
bridgehead carbon of the azabicyclo[2.2.n]alkane system.
Particularly, in the case of the 1-substituted 2-azabicyclo-
[2.2.2]octane system, a new synthetic route has been
developed, which involves the synthesis of a novel rigid
sulfamidate that allows the straightforward introduction of
nucleophiles.
(5) For recent examples, see: (a) Malpass, J. R.; Patel, A. B.; Davies,
J. W.; Fulford, S. Y. J. Org. Chem. 2003, 68, 9348-9355. (b) Malpass, J.
R.; White, R. J. Org. Chem. 2004, 69, 5328-5334. (c) Carroll, F. I.; Ma,
W.; Yokota, Y.; Lee, J. R.; Brieaddy, L. E.; Navarro, H. A.; Damaj, M. I.;
Martin, B. R. J. Med. Chem. 2005, 48, 1221-1228. (d) Carroll, F. I.;
Brieaddy, L. E.; Navarro, H. A.; Damaj, M. I.; Martin, B. R. J. Med. Chem.
2005, 48, 7491-7495. (e) Malpass, J. R.; Handa, S.; White, R. Org. Lett.
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A.-M.; Wasicak, J. T.; Pavlik, P. A.; Martin, Y. C.; Donnelly-Roberts,
D. L.; Anderson, D. J.; Sullivan, J. P.; Williams, M.; Arneric, S. P.;
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The design of ligands for the nicotinic acetylcholine receptors
(nAChRs) has experienced a great advance1 due to the isolation
and structural characterization of epibatidine as a potent
analgesic.2 Further studies showed that the analgesic activity
resulted from interaction with nicotinic acetylcholine receptors.3
The synthetic methodology developed for the synthesis of
epibatidine, along with its toxicity, provided the means for the
synthesis of a large number of epibatidine analogues, which
have been evaluated for their biological activity. These ana-
logues have provided interesting information concerning the
structure-activity relationship (SAR).4 As a result, several
structural modifications aimed at improving SAR4 have been
* Fax: +34 941 299621.
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L.; Daly, J. W. J. Am. Chem. Soc. 1992, 114, 3475-3478.
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Biftu, T.; Ip, S. Eur. J. Pharmacol. 1993, 250, R13-R14. (b) Badio, B.;
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10.1021/jo0700732 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/20/2007
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