Christoph Eibl1, Lenka Munoz, Isabelle Tomassoli, Clare Stokes, Roger L Papke, Daniela Gündisch. 1. Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany; Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA.
Abstract
3,7-Diazabicyclo[3.3.1]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 α4β2(∗) nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for α4β2(∗) nAChR. All evaluated compounds are partial agonists or antagonists at α4β2(∗), with reduced or no effects on α3β4(∗) with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes.
3,7-Diazabicyclo[3.3.1]nonane (n class="Chemical">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 α4β2(∗) nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for α4β2(∗) nAChR. All evaluated compounds are partial agonists or antagonists at α4β2(∗), with reduced or no effects on α3β4(∗) with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes.
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