2,5-Disubstituted pyridines : The discovery of a novel series of 5-HT2A ligands

This report describes the effect of replacing the central basic amine present in many known 5-HT(2A) ligands with an aromatic residue. We targeted the isomeric phenethylpyridines 2 and 3 and these compounds proved to be excellent leads, possessing good 5-HT(2A) receptor binding affinity and selectiv...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2007-05, Vol.17 (9), p.2643-2648
Main Authors: WILSON, Kevin J, VAN NIEL, Monique B, COOPER, Laura, BLOOMFIELD, Dawn, O'CONNOR, Desmond, FISH, L. Rebecca, MACLEOD, Angus M
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Chemistry, Pharmaceutical - methods
Drug Design
Humans
Kinetics
Ligands
Medical sciences
Models, Chemical
Molecular Conformation
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacology
Rats
Receptor, Serotonin, 5-HT2A - chemistry
Serotonin Antagonists - chemical synthesis
Serotonin Antagonists - chemistry
Serotonin Antagonists - pharmacology
Serotoninergic system
Sulfones - chemistry
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Summary:This report describes the effect of replacing the central basic amine present in many known 5-HT(2A) ligands with an aromatic residue. We targeted the isomeric phenethylpyridines 2 and 3 and these compounds proved to be excellent leads, possessing good 5-HT(2A) receptor binding affinity and selectivity over the 5-HT(2C) subtype. Optimization of one isomer led to the identification of 25, a compound with sub-nanomolar 5-HT(2A) affinity and selectivity over 5-HT(2C) of greater than 4600-fold.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2007.01.098