Synthesis of Conformationally Constrained Analogues of Epibatidine and Development of Non-opioidal Analgesics

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We have developed a synthetic method to prepare the conformationally constrained spirodihydrofuropyridines as syn-N-N and anti-N-N analogues of epibatidine, in which the 7-azabicyclo[2.2.1] heptane system and the 2-choropyridine ring are held rigidly with the shorter and longer N-N distances, respectively. The synthesis of the syn-N-N analogue was achieved via the reaction of N-Boc-7-azabicyclo[2.2.1]heptan-2-one with 2-chloro-5-lithio-4-methylpyridine to give the endo-alcohol as a single isomer, which underwent bromination with NBS, basic treatment to form the oxaspirocyclic compound, and deportection of the N-Boc group. The anti-N-N analogue was obtained in a similar way by using 6-chloro-3-lithio-2-methylpyridine.Binding assays conducted in brain membranes of male Wister rats by measuring the displacement of [3H]cytisine showed that the syn-N-N spiro analogue with the shorter N-N distance has at least two-fold stronger binding affinity (IC_<50> = 409 nM, Ki = 136 nM) for nAChRs than the anti-N-Nanalogue (IC_50 = >1000 nM) containing the longer internitrogen distance. The binding studies of these analogues imply that the epibatidine conformer with the shorter N-N distance is favored for high affinity for the central nicotinic acetylcholine binding sites, which would provide some insight into the development of a rational approach for the design and preparation of new ligands selective for the central nAChRs.