ABSTRACT
A novel series of 5,5-diaryl-2-amino-4-pentenoates was synthesized and found to be potent and selective glycine transporter type-2 reuptake inhibitors.
Subject(s)
Alkenes/pharmacology , Amino Acid Transport Systems, Neutral , Antimetabolites/pharmacology , Carrier Proteins/antagonists & inhibitors , Alkenes/chemical synthesis , Alkenes/chemistry , Antimetabolites/chemical synthesis , Antimetabolites/chemistry , Glycine Plasma Membrane Transport Proteins , Structure-Activity RelationshipABSTRACT
Sumatriptan, a h5-HT1D and h5-HT1B receptor agonist used clinically as a migraine-abortive, produces certain side effects thought to result from its affinity for h5-HT1B receptors. The present investigation extends our work with benzylimidazolines as novel non-tryptamine h5-HT(1D/1B) ligands. The effect of N-methylation, N-benzylation, ring-aromatization, and variation of the imidazoline ring on affinity both at h5-HT1D and h5-HT1B receptors was examined. Several compounds were identified with good affinity and enhanced (i.e., > 100-fold) h5-HT1D versus hS-HT1B selectivity.
Subject(s)
Benzyl Compounds/pharmacology , Imidazoles/pharmacology , Receptors, Serotonin/metabolism , Serotonin Agents/chemical synthesis , Serotonin Receptor Agonists/pharmacology , Benzyl Compounds/chemical synthesis , Benzyl Compounds/metabolism , Cell Membrane/chemistry , Cell Membrane/metabolism , Humans , Imidazoles/chemical synthesis , Imidazoles/metabolism , Ligands , Migraine Disorders/drug therapy , Protein Binding , Radioligand Assay , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Serotonin Agents/metabolism , Serotonin Agents/pharmacologyABSTRACT
N-Benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine (BS/5-OMe DMT; 5) was shown to bind at human 5-HT6 serotonin receptors with high affinity (Ki = 2.3 nM) relative to serotonin (Ki = 78 nM). Structural variation failed to result in significantly enhanced affinity. BS/5-OMe DMT acts as an antagonist of 5-HT-stimulated adenylate cyclase (pA2 = 8.88 nM) and may represent the first member of a novel class of 5-HT6 antagonists.
Subject(s)
Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Tryptamines/chemical synthesis , Adenylyl Cyclases/metabolism , Cell Line , Drug Design , Humans , Kinetics , Models, Molecular , Molecular Conformation , Radioligand Assay , Receptors, Serotonin/drug effects , Recombinant Proteins/antagonists & inhibitors , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Transfection , Tryptamines/chemistry , Tryptamines/pharmacologyABSTRACT
A series of 5-alkyltryptamines (6) and the corresponding conformationally constrained analogues (8) have been synthesized. The structure activity relationships (SAR) at the 5-position of the indole skeleton and the ethylamine side chain have been studied. Functional activities were assessed using isolated rabbit saphenous vein. Potent, selective ligands were found (6e, Ki 2.5 nM, 5-HT1B/5-HT1D 125-fold) that have potential for treating acute migraine.
Subject(s)
Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/pharmacology , Tryptamines/chemistry , Animals , In Vitro Techniques , Protein Binding , Rabbits , Receptor, Serotonin, 5-HT1D , Receptors, Serotonin/metabolism , Saphenous Vein/drug effects , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/metabolism , Tryptamines/metabolismABSTRACT
A novel series of 6-bicyclopiperazinyl-1-arylsulfonylindoles and 6-bicyclopiperidinyl-1-arylsulfonylindoles derivatives was synthesized and found to be potent and selective 5-HT6 receptor antagonists.
Subject(s)
Indoles/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Cell Line , Humans , Indoles/chemical synthesis , Indoles/chemistry , Indoles/metabolism , Piperazines/chemistry , Radioligand Assay , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/chemistry , Sulfones/chemistryABSTRACT
A series of 5-(2- or 3-thienyl)tryptamine derivatives (9) has been synthesized and shown to be potent and selective 5-HT1D versus 5-HT1B receptor agonists and, therefore, potential treatments for migraine.
Subject(s)
Migraine Disorders/drug therapy , Receptors, Serotonin/drug effects , Serotonin Antagonists/chemical synthesis , Tryptamines/chemical synthesis , Cloning, Molecular , Humans , Indicators and Reagents , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Tryptamines/pharmacologyABSTRACT
A series of pyrrolo[3,2,1-ij]quinoline derivatives was synthesized, evaluated for their activity against the 5-HT2c and 5-HT2a, receptors and found to be agonists at 5-HT2c with selectivity over 5-HT2a.