ABSTRACT
As part of our efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands for this purpose. Herein we report the identification of a novel series of 3-sulfonylindazole derivatives with acyclic amino side chains as potent and selective 5-HT(6) antagonists. The synthesis and detailed SAR of this class of compounds are reported.
Subject(s)
Indazoles/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , HeLa Cells , Humans , Indazoles/chemistry , Magnetic Resonance Spectroscopy , Nootropic Agents/chemistry , Nootropic Agents/pharmacology , Serotonin Antagonists/chemistry , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
Novel 5-cyclic amine-3-arylsulfonylindazoles were prepared, and several analogues within this class have been identified as high-affinity 5-HT(6) receptor ligands with improved pharmacokinetic and pharmacological properties. One selected example, 18b, showed good brain penetrability and a generally favorable pharmacokinetic profile with procognitive efficacy in the rat novel object recognition assay. The synthesis and structure-activity relationship of this potent class are discussed.
Subject(s)
Indazoles/metabolism , Receptors, Serotonin/metabolism , Serotonin Antagonists/metabolism , Sulfones/metabolism , Animals , Binding, Competitive , Brain/metabolism , Exploratory Behavior/drug effects , Habituation, Psychophysiologic/drug effects , Humans , Indazoles/chemistry , Indazoles/pharmacology , Models, Chemical , Molecular Structure , Rats , Receptor, Serotonin, 5-HT2B/chemistry , Receptor, Serotonin, 5-HT2B/metabolism , Receptors, Serotonin/chemistry , Recognition, Psychology/drug effects , Serotonin 5-HT2 Receptor Antagonists , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacokinetics , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
Synthesis of 2,3-substituted indoles from phenylhydrazine and alpha-branched aldehydes via rearrangement of 3,3-disubstituted indolenine intermediates is reported. [reaction: see text]
Subject(s)
Indoles/chemical synthesis , Aldehydes/chemistry , Catalysis , Magnetic Resonance Spectroscopy , Phenylhydrazines/chemistry , SolventsABSTRACT
Compounds containing a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2H-1-benzopyran and a 3-alkylindole moiety linked through a common basic nitrogen were prepared and evaluated for 5-HT1A affinity, serotonin rat transporter affinity, and functional antagonist activity in vitro. 26a was found to be the most potent and selective compound in this series and was shown to possess neurochemical activity in vivo by producing acute and rapid increases in 5-HT in the rat frontal cortex.
