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, α3ß2, α4ß2, α3ß4, or α4ß4. Characterization of selected compounds revealed eight inhibitors of the α7 nicotinic receptor and three positive allosteric modulators of the α3ß2 nAChR.
Subject(s)
Benzamides/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Nicotinic Agonists/chemical synthesis , Nicotinic Antagonists/chemical synthesis , 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 , XenopusABSTRACT
Palladium-catalyzed cross-coupling reactions have been investigated in multicatalytic processes to synthesize disubstituted alkenes and alkanes from carbonyl derivatives. The use of copper-catalyzed methylenation reactions is the key starting reaction to produce terminal alkenes which are not isolated, but submitted to further structure elongation. Not only is the isolation of the alkene intermediate unnecessary, but also the copper catalyst is a beneficial cocatalyst in the palladium-catalyzed cross-coupling reactions. The desired products are thus typically obtained in higher yields using this one-pot approach. We have used these processes to synthesize hydroxylated (E)-stilbenoids, which are known chemopreventive and chemotherapeutic agents, odorant-substituted indanes, and non-natural amino acids, such as homophenylalanine.