exo-2-(Pyridazin-4-yl)-7-azabicyclo[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 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 alpha4beta2 and alpha3beta4 subtypes.
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Institut für Pharmazeutische Chemie, Universität Marburg, Marbacher Weg 6, D-35032 Marburg/Lahn, Germany.
Wegge
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Stubbs
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Seitz
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Meier
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Methfessel
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D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D066298:In Vitro Techniques; D008024:Ligands; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D013237:Stereoisomerism; D014982:Xenopus laevis
C419400:2-(pyridazin-4-yl)-7-azabicyclo(2.2.1)heptane; C419401:7-methyl-2-(pyridazin-4-yl)-7-azabicyclo(2.2.1)heptane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D018722:Nicotinic Agonists; D011724:Pyridazines; D011725:Pyridines; C082748:epibatidine