ABSTRACT
A series of racemic 3-(trans-2-aminomethylcyclopentyl)indoles was synthesized and found to have potent binding to the human serotonin transporter (hSERT). The most active analog was synthesized stereospecifically and the active enantiomer was shown to have high affinity binding to hSERT.
Subject(s)
Indoles/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Tryptamines/chemistry , Animals , Antidepressive Agents/chemistry , Chemistry, Pharmaceutical/methods , Cyclopentanes/chemistry , Dose-Response Relationship, Drug , Humans , Inhibitory Concentration 50 , Ligands , Models, Chemical , Protein Binding , Rats , Serotonin/chemistry , 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
The present studies have identified a series of aminotriazines as novel 5-HT(7) receptor antagonists. Compounds 10 and 17 have high affinity for the 5-HT(7) receptor and do not bind to either the 5-HT(2C) or 5-HT(6) receptors. These compounds produce no agonist effects by themselves, and shift the dose-response curve of 5-CT to the right in the manner of an antagonist.
Subject(s)
Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Triazines/pharmacology , Dose-Response Relationship, DrugABSTRACT
Bivalent doxorubicin (DOX)-dipeptides (16a-c) were prepared and conjugated to the monoclonal antibody BR96. The dipeptides are cleaved by lysosomal proteases following internalization of the resulting immunoconjugates. Conjugate 18b demonstrated antigen-specific in vitro tumor cell killing activity (IC(50)=0.2 microM) that was equipotent to DOX with a near doubling of drug molecules/MAb. Size exclusion chromatography showed 18b to be a noncovalent dimer that was formed immediately upon conjugation.
