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

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 K i 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.