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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).
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2012 May 24; Vol. 55 (10), pp. 4605-18. Date of Electronic Publication: 2012 May 16. - Publication Year :
- 2012
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Abstract
- 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.
- Subjects :
- Allosteric Regulation
Animals
Benzamides chemistry
Benzamides pharmacology
Binding Sites
Bridged Bicyclo Compounds chemistry
Bridged Bicyclo Compounds pharmacology
Bridged Bicyclo Compounds, Heterocyclic chemistry
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Databases, Factual
Female
Humans
Models, Molecular
Nicotinic Agonists chemistry
Nicotinic Agonists pharmacology
Nicotinic Antagonists chemistry
Nicotinic Antagonists pharmacology
Oocytes drug effects
Oocytes physiology
Patch-Clamp Techniques
Receptors, Nicotinic chemistry
Receptors, Nicotinic metabolism
Stereoisomerism
Structure-Activity Relationship
Xenopus
Benzamides chemical synthesis
Bridged Bicyclo Compounds chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic chemical synthesis
Nicotinic Agonists chemical synthesis
Nicotinic Antagonists chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 55
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22591063
- Full Text :
- https://doi.org/10.1021/jm300030r