exo-2-(Pyridazin-4-yl)-7-azabicyclo[2.2.1]heptanes: Syntheses and Nicotinic
Acetylcholine Receptor Agonist Activity of Potent Pyridazine Analogues of
(±)-Epibatidine
posted on 2000-11-30, 00:00authored byDaqing Che, Thomas Wegge, Milton T. Stubbs, Gunther Seitz, Heinrich Meier, Christoph Methfessel
A new strategy for the straightforward synthesis of novel racemic epibatidine analogues is
presented, in which the 2-chloropyridinyl moiety of epibatidine is bioisosterically replaced by
differently substituted pyridazine rings. A key step of the new syntheses is the inverse type
Diels−Alder reaction of the electron-rich enol ether 13 with the electron-deficient diazadiene
systems of the 1,2,4,5-tetrazines 14a−d to yield the novel pyridazine analogues of (±)-epibatidine 18, 19, 22, and 24. In addition preparation of the N-substituted derivatives, such
as 26 and 28, is described. The structures of the novel epibatidine analogues were assigned on
the basis of spectral data, that of compound 24 being additionally verified by X-ray
crystallography exhibiting two racemic solid-state conformations in the crystal lattice and
representing the first X-ray structure of an unprotected 7-azabicyclo[2.2.1]heptane moiety. The
nAChR agonist activity of the racemic compounds 18, 19, 22, 24, and 28 was assayed in vitro
by whole-cell current recordings from Xenopus oocytes expressing different recombinant nicotinic
receptors from the rat. Among the compounds synthesized and tested, the pyridazine analogue
24 of (±)-epibatidine and its N-methyl derivative 28 were found to be the most active ones
retaining much of the potency of natural epibatidine but with a substantially improved
selectivity ratio between the α4β2 and α3β4 subtypes.