Nicotinic acetylcholine receptor ligands from 2,4-methanoproline derivatives
thesisposted on 15.12.2014, 10:35 by Anup B. Patel
Since the discovery of the powerful analgesic epibatidine in 1974 from the Ecuadorian poison frog Epipedobates tricolor, there has been global interest in the synthesis of analogue molecules. Epibatidine has the unique 7-azabicyclo[2.2.1]heptane structure with a chloropyridyl ring at the 2-positon. Epibatidine acts at the nicotinic acetylcholine receptor (nAChR) and the aim of this work is to produce target compounds retaining therapeutic potential but with higher nAChR sub-type selectivity and lower toxicity. The only naturally occurring compound to have the 2-azabicyclo[2.1.1]hexane system is the nonproteinogenic amino acid 2,4-methanoproline. This alternative bicyclic framework opens the route to the construction of pioneering epibatidine analogues. The intramolecular [2+2] photocycloaddition method was employed to construct the rigid 2-azabicyclo[2.1.1]hexane skeleton. Successful nucleophilic substitution at a methylene attached to the bridgehead position of the 2-azabicyclo[2.1.1]hexane ring system opened the way to construction of innovative derivatives. These have a wider range of functional groups attached at the 1-positon via a methylene 'spacer' and provide access to epibatidine analogues containing heterocyclic substituents and to further homologation. Mechanistic studies indicate that displacements with loss of a nucleofuge require thermal activation but proceed without the rearrangement initially anticipated in such a strained bicyclic structure. A unique tricyclic carbamate has been isolated; nucleophilic attack on this carbamate leads directly to the isolation of N-deprotected substitution products with concomitant decarboxylation. The analogues produced in this study are currently being pharmacologically tested and the results will determine the course of future synthetic approaches towards original targets.