Synthesis and Nicotinic Binding Studies on Enantiopure Diazine Analogues of the Novel (2-Chloro-5-pyridyl)-9-azabicyclo[4.2.1]non-2-ene UB-165

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Abstract
As part of our program aimed at optimizing therapeutic effects over toxic effects (as observed in the naturally occurring nicotinic acetylcholine receptor modulators (−)-nicotine, (−)-epibatidine, (−)-ferruginine, and (+)-anatoxin-a), we investigated the bioisosteric potential of diazines in the field of (+)-anatoxin-a-type structures. In the series of diazine analogues of deschloro-UB-165 (DUB-165, 6), bioisosteric replacement of the 3-pyridyl pharmacophoric element by a 4-pyridazinyl, 5-pyrimidinyl, or 2-pyrazinyl moiety resulted in novel nAChR ligands 7, 8, and 9. A palladium-catalyzed Suzuki cross-coupling of the 3-diethylboranylpyridine (14) and a Stille cross-coupling of the corresponding tributylstannyl diazines 15 − 17 with the vinyl triflate 13 of the N-protected 9-azabicyclo[4.2.1]nonan-2-one 12 constitute the key steps in the syntheses of these enantiopure anatoxinoids 6 − 9. Studies of the in vitro affinity for (α4)2(β2)3, α3β4*, and α7* nAChR subtypes by radioligand binding assays demonstrated that the diazine analogues 7 − 9 can be considered as pharmacologically attractive bioisosteres of DUB-165 (6) but with different effects on the binding affinity with regard to the diazine moiety. The pyrimidine-containing bioisostere 8 turned out to be the most active diazine analogue, which interacts potently (Ki = 0.14 nM) with the (α4)2(β2)3 subtype and differentiates significantly among the nAChR subtypes investigated. The nitrogens in this anatoxinoid 8 show by far the most negative atomic charges (calculated using the AM1 Hamiltonian). This qualitatively correlates with the highest binding affinity observed for 8 for all subtypes under consideration.