The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: Carboxamide derivatives with different spacer motifs |
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| Authors: | Christoph Eibl Lenka Munoz Isabelle Tomassoli 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-53121 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 (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4β21 nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for α4β21 nAChR. All evaluated compounds are partial agonists or antagonists at α4β21, with reduced or no effects on α3β41 with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes. |
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| Keywords: | 3 7-Diazabicyclo[3 3 1]nonane Bispidine Nicotinic acetylcholine receptor nAChR Structure–activity relationship Cytisine |
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