ABSTRACT
1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which 6f and 6g showed high affinity for 5-HT(6) receptors with K(i)=3.9 and 1.7 nM, respectively.
Subject(s)
Pyridines/pharmacology , Pyrroles/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , HeLa Cells , Humans , Ligands , Pyridines/chemistry , Pyrroles/chemistry , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Receptor Agonists/chemistryABSTRACT
A series of 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a-z was prepared as novel 5-HT(6) ligands. The best compounds were high affinity, full agonists at 5-HT(6) receptors. Several agonists demonstrated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders.
Subject(s)
Cerebral Cortex/drug effects , Drinking Behavior/drug effects , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Animals , Cerebral Cortex/metabolism , Glutamic Acid/analysis , Glutamic Acid/metabolism , HeLa Cells , Humans , Protein Binding , Rats , Serotonin Receptor Agonists/administration & dosage , Serotonin Receptor Agonists/chemical synthesis , gamma-Aminobutyric Acid/analysis , gamma-Aminobutyric Acid/metabolismABSTRACT
Novel compounds combining a 5-HT 1A moiety (3-aminochroman scaffold) and a 5-HT transporter (indole analogues) linked through a common basic nitrogen via an alkyl chain attached at the 1- or 3-position of the indole were evaluated for dual affinity at both the 5-HT reuptake site and the 5-HT 1A receptor. Compounds of most interest were found to have a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2 H-1-benzopyran linked to a 3-alkylindole (straight chain), more specifically substituted with a 5-fluoro (( R)-(-)- 35c), 5-cyano ((-)- 52a), or 5,7-difluoro ((-)- 52g). Several factors contributed to 5-HT 1A affinity, serotonin rat transporter affinity, and functional antagonism in vitro. Although most of our analogues showed good to excellent affinities at both targets, specific features such as cyclobutyl substitution on the basic nitrogen and stereochemistry at the 3-position of the chroman moiety seemed necessary for antagonism at the 5-HT 1A receptor. Branched linkers seemed to impart antagonism even as racemates; however, the potency of these analogues in the functional assay was not desirable enough to further pursue these compounds.
Subject(s)
Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacology , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , Antidepressive Agents/chemistry , Benzopyrans/chemistry , Cell Line , Cricetinae , Cross-Linking Reagents/chemistry , Humans , Molecular Structure , Rats , Receptor, Serotonin, 5-HT1A/metabolism , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Novel 1-(2-aminoethyl)-3-(arylsulfonyl)-1H-indoles were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which N,N-dimethyl-N-(2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl)amine 8t and N-methyl-N-(2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl)amine 8u showed high affinity for 5-HT(6) receptors with K(i)=3.7 and 5.7 nM, respectively.
