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
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
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
The design, synthesis, and structure-activity relationship of two novel classes of benzoxazine derivatives with dual selective serotonin reuptake inhibitors and 5-HT(1A) receptor activities are described.
Subject(s)
Antidepressive Agents/chemical synthesis , Antidepressive Agents/metabolism , Benzoxazines/chemistry , Benzoxazines/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Benzoxazines/chemical synthesis , Benzoxazines/pharmacology , Humans , Molecular Structure , Rats , Structure-Activity Relationship , Substrate SpecificityABSTRACT
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.