Conformationally restrained carbamoylcholine homologues. Synthesis, pharmacology at neuronal nicotinic acetylcholine receptors and biostructural considerations

Exploration of small selective ligands for the nicotinic acetylcholine receptors (nAChRs) based on acetylcholine (ACh) has led to the development of potent agonists with clear preference for the α4β2 nAChR, the most prevalent nAChR subtype in the central nervous system. In this work we present the continuation of these efforts aimed at increasing this subtype selectivity by introduction of conformational restriction in the carbamoylcholine homologue, 3-(dimethylaminobutyl) dimethylcarbamate (DMABC). Our results highlight the importance of the N-carbamoyl substitution in α4β2-subtype selectivity. Moreover, we have confirmed the non-linear conformation of DMABC bound to nAChRs suggested by recent crystal structures of the compound in complex with the Lymnaea stagnalis ACh binding protein.
M. F. R. gratefully acknowledges Dr. María Isabel Rodríguez- Franco, the fi nancial support of the Spanish Ministry of Economy and Competitiveness (project SAF2012-31035) and CSIC and Euro- pean Social Fund for a JAE-Predoctoral Contract (Grant JAE-Pre- 2009-106) and travel grant support. The stable cell lines expressing the nAChRs were kind gifts from Drs. J.A. Stitzel, J.H. Steinbach and K. Kellar. This study was supported fi nancially by the Novo Nordisk Foundation