J Med Chem 2012 May 24;5510:4605-18. doi: 10.1021/jm300030r.

Synthesis and nicotinic receptor activity of chemical space analogues of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU-282,987) and 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid 4-bromophenyl ester (SSR180711).

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The Chemical Universe Generated Databases up to 11 atoms of CNOF (GDB-11) and up to 13 atoms of CNOClS (GDB-13) were used to enumerate analogues of the diamine part of two known α7 nicotinic receptor agonists and construct libraries of virtual analogues of these drugs. The libraries were scored using structure-based (docking to the nicotine binding site of the acetylcholine binding protein 1uw6.pdb) or ligand-based (similarity to the parent drugs) methods, and the top-scoring virtual ligands were inspected for easily accessible synthetic targets. In total, 21 diamines were prepared and acylated with aromatic carboxylic or oxycarbonic acids to produce 85 analogues of the parent drugs. The compounds were profiled by electrophysiology in Xenopus oocytes expressing human nicotinic acetylcholine receptor (nAChR) subtypes α7, α3β2, α4β2, α3β4, or α4β4. Characterization of selected compounds revealed eight inhibitors of the α7 nicotinic receptor and three positive allosteric modulators of the α3β2 nAChR.

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