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The 3,7-diazabicyclo[3.3.1]nonane Scaffold for Subtype Selective Nicotinic Acetylcholine Receptor (nAChR) Ligands. Part 1: The Influence of Different Hydrogen Bond Acceptor Systems on Alkyl and (Hetero)aryl Substituents

The 3,7-diazabicyclo[3.3.1]nonane Scaffold for Subtype Selective Nicotinic Acetylcholine Receptor (nAChR) Ligands. Part 1: The Influence of Different Hydrogen Bond Acceptor Systems on Alkyl and (Hetero)aryl Substituents

Christoph Eibl, Isabelle Tomassoli, Lenka Munoz, Clare Stokes, Roger L Papke, Daniela Gündisch

Bioorg Med Chem. 2013 Dec 1;21(23):7283-308.

PMID: 24156938

Abstract:

3,7-Diazabicyclo[3.3.1]nonane is a naturally occurring scaffold interacting with nicotinic acetylcholine receptors (nAChRs). When one nitrogen of the 3,7-diazabicyclo[3.3.1]nonane scaffold was implemented in a carboxamide motif displaying a hydrogen bond acceptor (HBA) functionality, compounds with higher affinities and subtype selectivity for α4β2(∗) were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for α4β2(∗) possessed small alkyl chains, small un-substituted hetero-aryl groups or para-substituted phenyl ring systems along with a carboxamide group. Electrophysiological responses of selected 3,7-diazabicyclo[3.3.1]nonane derivatives to Xenopus oocytes expressing various nAChR subtypes showed diverse activation profiles. Compounds with strongest agonistic profiles were obtained with small alkyl groups whereas a shift to partial agonism/antagonism was observed for aryl substituents.

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