The twin drug approach for novel nicotinic acetylcholine receptor ligands

The association of two pharmacophoric entities generates so-called 'twin drugs' or dimer derivatives. We applied this approach for the design of a small compound library for the interaction with alpha 4 beta 2* nicotinic acetylcholine receptors (nAChRs). In this compound series, the nAChR ligand N, N-dimethyl-2-(pyridin-3-yloxy) ethan-1-amine 9 served as one pharmacological entity and it was initially kept constant as one part of the 'twin' compound. 'Twin' compounds with identical or non-identical entities using the 'no linker mode' or 'overlap' mode were synthesized and evaluated for their nAChR affinities. Compound 17a showed the highest affinity for the alpha 4 beta 2* nAChR subtype (K-i = 0.188 nM) and its (di)fluoro analogs could retain nanomolar affinities, when replacing pyridine as the hydrogen bond acceptor system by mono-or difluoro-phenyls. The 'twin drug' approach proved to provide compounds with high affinity and subtype selectivity for alpha 4 beta 2* nAChRs. (C) 2015 Elsevier Ltd. All rights reserved.