ABSTRACT
The identification of novel orally active mGluR5 antagonist GSK2210875 is described.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemistry , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Administration, Oral , Allosteric Regulation , Animals , Brain/drug effects , Brain/metabolism , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Mice , Rats , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity RelationshipABSTRACT
Lead optimisation starting from the previously reported selective quinoline NK(3) receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK(3) antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK(3) receptor antagonists which despite having different degrees of CNS penetration produced excellent NK(3) receptor occupancy in an ex vivo binding study in gerbil cortex.
Subject(s)
Central Nervous System/drug effects , Quinolines/chemical synthesis , Receptors, Neurokinin-3/antagonists & inhibitors , Amines/metabolism , Animals , Area Under Curve , Brain/metabolism , Cerebral Cortex/embryology , Gerbillinae , Male , Models, Chemical , Quinolines/metabolism , Quinolines/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
Investigation of halogen substitution in lead compound 1 has led to the identification of analogues which combine high affinity for 5-HT(1A) receptors and potent serotonin reuptake inhibitory activity. Several compounds show an improved selectivity over 5-HT(1B) and 5-HT(1D) receptors and a superior pharmacokinetic profile in the rat.
Subject(s)
Benzoxazines/chemical synthesis , Benzoxazines/pharmacology , Receptor, Serotonin, 5-HT1A/drug effects , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Animals , Binding, Competitive/drug effects , CHO Cells , Callithrix , Cell Line , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cricetinae , Cricetulus , Guinea Pigs , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Piperazines/pharmacology , Pyridines/pharmacology , Radioligand Assay , Rats , Receptor, Serotonin, 5-HT1B/drug effects , Receptor, Serotonin, 5-HT1D/drug effects , Synaptosomes/drug effectsABSTRACT
Bisaryl cyclic ureas have been identified as high affinity 5-HT2C receptor antagonists with selectivity over 5-HT2A and 5-HT2B. Compounds such as 8 and 22 have shown oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function in rodents.
