ABSTRACT
Racemic 5-(trans-2-aminomethylcyclopropyl)indoles, 5-(trans-2-aminomethylcyclopentyl) indoles, and 5-(cis-2-aminomethylcyclopentyl)indoles were synthesized and evaluated as selective serotonin reuptake inhibitors. These analogs followed SAR trends similar to those previously reported for 3-cycloalkyl substituted indoles. The most potent analogs exhibited single digit nanomolar inhibition at the human serotonin transporter but were 10-fold less active than the previously reported compounds.
Subject(s)
Methylamines/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Plasma Membrane Transport Proteins/metabolism , Dose-Response Relationship, Drug , Humans , Methylamines/chemical synthesis , Methylamines/chemistry , Molecular Conformation , Molecular Structure , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
A series of hybrid molecules containing the cyclopropylmethylamino side chain found in homotryptamine (1S,2S)-2c and an isosteric heteroaryl or naphthyl core were prepared and their binding affinities for the human serotonin transporter determined. The most potent isosteres were CN-substituted naphthalenes. These results demonstrate that isosteric aromatic cores which lack an H-bond donor site may be substituted for the indole nucleus without substantial loss in hSERT binding.
Subject(s)
Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Tryptamines/chemistry , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Plasma Membrane Transport Proteins/metabolism , Heterocyclic Compounds/chemical synthesis , Humans , Inhibitory Concentration 50 , Molecular Conformation , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Structure-Activity RelationshipABSTRACT
A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a. The enantiomers of 6a were energy minimized and compared to other conformationally restricted SSRIs. Compound 6a was found to give a dose-response similar to the SSRI fluoxetine in microdialysis studies in rats.
Subject(s)
Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Tryptamines/chemistry , Animals , Cyclohexenes/chemical synthesis , Cyclohexenes/chemistry , Cyclohexenes/pharmacology , Fluoxetine/chemistry , Fluoxetine/pharmacology , Humans , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Microdialysis , Molecular Conformation , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Rats , Selective Serotonin Reuptake Inhibitors/chemical synthesisABSTRACT
A series of fluoren-9-yl ethyl amides (2) were synthesized and evaluated for human melatonin MT(1) and MT(2) receptor binding. N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]propanamide (2b) was selected and evaluated in functional assays measuring intrinsic activity at the human MT(1) and MT(2) receptors and demonstrated full agonism at both receptors. The chronobiotic properties of 2b were demonstrated in both acute and chronic rat models where 2b produced an acute phase advance of 32 min at 1mg/kg and chronically entrained free-running rats with a mean effective dose of 0.23 mg/kg. Compound 2b is significantly less efficacious than melatonin in constricting human coronary artery.
Subject(s)
Chronobiology Phenomena/physiology , Fluorenes/chemistry , Melatonin/metabolism , Amides/chemical synthesis , Amides/pharmacology , Animals , Binding Sites , Dose-Response Relationship, Drug , Humans , Mice , NIH 3T3 Cells , Radioligand Assay , Rats , Receptors, Melatonin/metabolism , Structure-Activity RelationshipABSTRACT
A series of benzoxazole derivatives was synthesized and evaluated as melatoninergic ligands. The binding affinity of these compounds for human MT(1) and MT(2) receptors was determined using 2-[(125)I]-iodomelatonin as the radioligand. From this series of benzoxazole derivatives, compounds 14 and 17 were identified as melatonin receptor agonists.
Subject(s)
Benzoxazoles/chemical synthesis , Receptors, Melatonin/agonists , Benzoxazoles/pharmacology , Binding Sites , Cell Line , Drug Design , Humans , Ligands , Melatonin/analogs & derivatives , Melatonin/metabolism , Radioligand Assay , Receptors, Cell Surface/drug effects , Receptors, Melatonin/metabolism , Structure-Activity RelationshipABSTRACT
A series of 4-substituted anilides with human melatonergic affinity is reported. Butyramides 26, 39, 42, 52, 57, and 58 all demonstrated subnanomolar MT(2) binding affinity and MT(2) selectivity of at least 70-fold over the MT(1) receptor. Compound 26 demonstrated full agonism at the MT(2) receptor.
Subject(s)
Anilides/chemistry , Receptor, Melatonin, MT2/agonists , Anilides/chemical synthesis , Binding, Competitive , Humans , Melatonin/metabolism , Molecular Structure , Receptor, Melatonin, MT2/chemistry , Structure-Activity RelationshipABSTRACT
A series of chiral heterocyclic aminopyrrolidine derivatives was synthesized as novel melatoninergic ligands. Binding affinity assays were performed on cloned human MT(1) and MT(2) receptors, stably expressed in NIH3T3 cells. Compound 16 was identified as an orally bioavailable agonist at MT(1) and MT(2) melatonin receptors with low vasoconstrictive activity.
