exo-2-(pyridazin-4-yl)-7-azalbicyclo[2.2.1]heptanes: Syntheses and nicotinic acetylcholine receptor agonist activity of potent pyridazine analogues of (+/-)-epibatidine

A new strategy for the straightforward synthesis of novel racemic epibatidi ne analogues is presented, in which the 2-chloropyridinyl moiety of epibati dine is bioisosterically replaced by differently substituted pyridazine rin gs. A key step of the new syntheses is the inverse type Diels-Alder reactio n 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 anal ogues of (+/-)epibatidine 18, 19, 22, and 24. In addition preparation of th e N-substituted derivatives, such as 26 and 28, is described. The structure s of the novel epibatidine analogues were assigned on the basis of spectral data, that of compound 24 being additionally verified by X-ray crystallogr aphy exhibiting two racemic solid-state conformations in the crystal lattic e 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 recording s from Xenopus oocytes expressing different recombinant nicotinic receptors from the rat. Among the compounds synthesized and tested, the pyridazine a nalogue 24 of(+/-)-epibatidine and its N-methyl derivative 28 were found to be the most active ones retaining much of the: potency of natural epibatid ine but with a substantially improved selectivity ratio between the alpha4 beta2 and alpha3 beta4 subtypes.