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 |
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| Authors: | Christoph Eibl Isabelle Tomassoli Lenka Munoz Clare Stokes Roger L Papke Daniela Gündisch |
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| Institution: | 1. Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-533121 Bonn, Germany;2. Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA;3. Department of Pharmacology, School of Medical Sciences, The University of Sydney, NSW 2006, Australia;4. Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA |
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| Abstract: | 3,7-Diazabicyclo3.3.1]nonane is a naturally occurring scaffold interacting with nicotinic acetylcholine receptors (nAChRs). When one nitrogen of the 3,7-diazabicyclo3.3.1]nonane scaffold was implemented in a carboxamide motif displaying a hydrogen bond acceptor (HBA) functionality, compounds with higher affinities and subtype selectivity for α4β21 were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for α4β21 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-diazabicyclo3.3.1]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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| Keywords: | 3 7-Diazabicyclo[3 3 1]nonane Bispidine Nicotinic acetylcholine receptor nAChR Structure–activity relationship |
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