H. Gohlke, D. Gündisch, S. Schwarz
Feb 5, 2002
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0
Influential Citations
49
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Quality indicators
Journal
Journal of medicinal chemistry
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 (alpha4)(2)(beta2)(3), alpha3(beta)4, and alpha7 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 (K(i) = 0.14 nM) with the (alpha4)(2)(beta2)(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.