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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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2007-05, Vol.17 (9), p.2643-2648
Hauptverfasser:	WILSON, Kevin J, VAN NIEL, Monique B, COOPER, Laura, BLOOMFIELD, Dawn, O'CONNOR, Desmond, FISH, L. Rebecca, MACLEOD, Angus M
Format:	Artikel
Sprache:	eng
Schlagworte:	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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Zusammenfassung:	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