ABSTRACT
Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were prepared and evaluated for serotonin transporter and 5-HT(1A) receptor affinities. Their design, synthesis and structure-activity relationships are described.
Subject(s)
Benzofurans/chemistry , Benzofurans/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Protein Binding/physiology , Structure-Activity RelationshipABSTRACT
The structure-activity relationship (SAR) for three series of lactam-fused chroman derivatives possessing 3-amino substituents was evaluated. Many compounds exhibited affinities for both the 5-HT(1A) receptor and the 5-HT transporter. Compounds 45 and 53 demonstrated 5-HT(1A) antagonist activities in the in vitro cAMP turnover model.
Subject(s)
Chromans/chemistry , Lactams/chemistry , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Serotonin Plasma Membrane Transport Proteins/metabolism , Chromans/chemical synthesis , Chromans/pharmacology , Cyclic AMP/metabolism , Drug Design , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Plasma Membrane Transport Proteins/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
On the basis of the previously reported clinical candidate, SSA-426 (1), a series of related 2-piperazin-1-ylquinoline derivatives 3-16 were synthesized and evaluated as dual-acting serotonin (5-HT) reuptake inhibitors and 5-HT1A receptor antagonists. In particular, compound 7 exhibits potent functional activities at both the 5-HT transporter and 5-HT1A receptor, good selectivity over the alpha1-adrenergic and dopaminergic receptors, acceptable pharmacokinetic properties, and a favorable in vivo profile.
Subject(s)
Piperazines/chemical synthesis , Quinolines/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Serotonin Antagonists/chemical synthesis , Animals , Antidepressive Agents/pharmacology , CHO Cells , Cricetinae , Cricetulus , Cytochrome P-450 Enzyme Inhibitors , Humans , Microdialysis , Piperazines/pharmacology , Quinolines/pharmacology , Rats , Receptors, Adrenergic, alpha-1/metabolism , Receptors, Dopamine/metabolism , Serotonin Antagonists/pharmacokinetics , Serotonin Antagonists/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
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
Based on the previously reported discovery lead, 3-(cis-4-(4-(1H-indol-4-yl)piperazin-1-yl)cyclohexyl)-5-fluoro-1H-indole (2), a series of related arylpiperazin-4-yl-cyclohexyl indole analogs were synthesized then evaluated as 5-HT transporter inhibitors and 5-HT(1A) receptor antagonists. The investigation of the structure-activity relationships revealed the optimal pharmacophoric elements required for activities in this series. The best example from this study, 5-(piperazin-1-yl)quinoline analog (trans-20), exhibited equal binding affinities at 5-HT transporter (K(i)=4.9nM), 5-HT(1A) receptor (K(i)=6.2nM) and functioned as a 5-HT(1A) receptor antagonist.
Subject(s)
Antidepressive Agents/chemistry , Indoles/chemistry , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , Cyclohexylamines , Humans , Indoles/metabolism , Indoles/pharmacology , Piperazines , Serotonin 5-HT1 Receptor Antagonists , Structure-Activity RelationshipABSTRACT
Structural modifications of the initial lead, 3-aminochroman (4), led to the identification of a novel series of pyridyl-fused amino chroman derivatives (5-8) and the structural isomers (9-12). The compounds described were evaluated for dual 5-HT transporter inhibitory and 5-HT(1A) receptor activities. The design strategy, synthesis, and in vitro biological characterization for these novel compounds are described.
Subject(s)
Chromans/chemistry , Chromans/pharmacology , Receptor, Serotonin, 5-HT1A/drug effects , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Plasma Membrane Transport Proteins/drug effects , Animals , Humans , Rats , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesisABSTRACT
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.
Subject(s)
Antidepressive Agents/chemical synthesis , Benzopyrans/chemical synthesis , Chromans/chemical synthesis , Indoles/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Benzopyrans/chemistry , Benzopyrans/pharmacology , CHO Cells , Chromans/chemistry , Chromans/pharmacology , Cricetinae , Cricetulus , Frontal Lobe/drug effects , Frontal Lobe/metabolism , Humans , Indoles/chemistry , Indoles/pharmacology , Microdialysis , Radioligand Assay , Rats , Serotonin/biosynthesis , Serotonin 5-HT1 Receptor Agonists , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Derivatives of the serotonin reuptake inhibitor 4-(5-fluoro-1H-indol-3-yl)cyclohexylamine, in which serotonin 1A (5-HT(1A)) receptor pharmacophoric elements are incorporated, are reported. Analogs exhibiting affinity for both the serotonin transporter and the 5-HT(1A) receptor are described. Compounds containing 1-(4-indolyl)piperazine and 2-(1H-indol-4-yloxy)ethylamine are promising leads for further SAR studies.