The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: Carboxamide derivatives with different spacer motifs

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 alpha 4 beta 2* nAChR. Compounds 15, 25, and 47 with K-i values of about 1 nM displayed the highest affinities for alpha 4 beta 2* nAChR. All evaluated compounds are partial agonists or antagonists at alpha 4 beta 2*, with reduced or no effects on alpha 3 beta 4* with the exception of compound 15 (agonist), and reduced or no effect at alpha 7 and muscle subtypes. (C) 2013 Elsevier Ltd. All rights reserved.