Synthesis and binding affinity at neuronal nicotinic acetylcholine receptors of novel epibatidine-related delta2-isoxazoline derivatives

Neuronal nicotinic acetylcholine receptors (nAChRs) are involved in a number of functional processes as well as several pathological conditions of the central nervous system, thereby representing a target for the development of novel therapeutic agents [1]. In the last few years many efforts have been directed towards the discovery of potent and selective nAChR ligands, in particular agonists at alpha4beta2 or alpha7 receptor subtypes, which are the two major populations of nAChRs found in the brain. In this context, epibatidine, a naturally occurring alkaloidal toxin which is one of the most powerful nicotinic agonists known, has become a model structure for the design of new high affinity and subtype selective ligands for nAChRs [2,3]. We designed and synthesized a set of novel compounds (1a-c and 2a-c), in which the two structural elements featuring epibatidine, i.e. the 7-azabicyclo[2.2.1]heptane system and the pyridine ring, have been distanced by insertion of a Delta2-isoxazoline moiety, either spiro-condensed or fused to the azanorbornane core, respectively. In addition, we designed compounds 3a-c as simplified analogues of derivatives 2a-c, where the ethylene bridge of the bicyclic system has been removed. The overall binding data evaluated on derivatives 1-3 indicated a relevant reduction of the alpha4beta2 affinity, typical of ebipatidine, coupled to the appearance of a noticeable affinity for the alpha7 receptor subtype. The results of further structural modifications on the compounds under investigation will be presented and discussed. [1] Paterson, D.; Nordberg, A. Neuronal Nicotinic Receptors in the Human Brain. Progr. Neurobiol. 2000; 61: 75-111. [2] Carroll, F. I. Epibatidine Structure-Activity Relationships. Bioorg. Med. Chem. Lett. 2004; 14: 1889-1896. [3] Wei, Z-L.; Petukhov, Y. X.; Tückmantel, W.; George, C.; Kellar, K. J.; Kozikowski, A. P. Synthesis, Nicotinic Acetylcholine Receptor Binding Affinities, and Molecular Modeling of Constrained Epibatidine Analogues. J. Med. Chem. 2003; 46: 921-924.