RESUMEN
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.
Asunto(s)
Indoles/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Triptaminas/química , Animales , Antidepresivos/química , Química Farmacéutica/métodos , Ciclopentanos/química , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Ligandos , Modelos Químicos , Unión Proteica , Ratas , Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Triptaminas/química , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Compuestos Heterocíclicos/síntesis química , Humanos , Concentración 50 Inhibidora , Conformación Molecular , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Triazinas/farmacología , Relación Dosis-Respuesta a DrogaRESUMEN
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.
