RESUMEN
(R)-2-(4-Phenylbutyl)dihydrobenzofuran derivatives (e.g., 3 and 4) were synthesized as novel melatoninergic ligands with significantly lower vasoconstrictive activity in vitro in the rat tail artery. Binding affinity assays were performed on cloned human MT1 and MT2 receptors stably expressed in NIH3T3 cells.
Asunto(s)
Benzofuranos/química , Benzofuranos/farmacología , Melatonina/agonistas , Vasoconstrictores/química , Vasoconstrictores/farmacología , Animales , Benzofuranos/síntesis química , Clonación Molecular , Humanos , Ligandos , Melatonina/farmacología , Ratones , Estructura Molecular , Células 3T3 NIH , Unión Proteica/efectos de los fármacos , Ratas , Receptor de Melatonina MT1/efectos de los fármacos , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/efectos de los fármacos , Receptor de Melatonina MT2/metabolismo , Proteínas Recombinantes/efectos de los fármacos , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/síntesis químicaRESUMEN
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.
Asunto(s)
Fenómenos Cronobiológicos/fisiología , Fluorenos/química , Melatonina/metabolismo , Amidas/síntesis química , Amidas/farmacología , Animales , Sitios de Unión , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Células 3T3 NIH , Ensayo de Unión Radioligante , Ratas , Receptores de Melatonina/metabolismo , Relación Estructura-ActividadRESUMEN
N-[2-[2-(4-Phenylbutyl)benzofuran-4-yl]cyclopropylmethyl]acetamide 3a was synthesized as an orally bioavailable agonist at MT1 and MT2 melatonin receptors with significantly low vasoconstrictive activity.
Asunto(s)
Acetamidas/farmacocinética , Benzofuranos/farmacocinética , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT2/agonistas , Acetamidas/síntesis química , Acetamidas/toxicidad , Administración Oral , Animales , Benzofuranos/síntesis química , Benzofuranos/toxicidad , Disponibilidad Biológica , AMP Cíclico/antagonistas & inhibidores , AMP Cíclico/biosíntesis , Relación Dosis-Respuesta a Droga , Humanos , Técnicas In Vitro , Ratones , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Células 3T3 NIH , Ensayo de Unión Radioligante , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Benzoxazoles/síntesis química , Receptores de Melatonina/agonistas , Benzoxazoles/farmacología , Sitios de Unión , Línea Celular , Diseño de Fármacos , Humanos , Ligandos , Melatonina/análogos & derivados , Melatonina/metabolismo , Ensayo de Unión Radioligante , Receptores de Superficie Celular/efectos de los fármacos , Receptores de Melatonina/metabolismo , Relación Estructura-ActividadRESUMEN
A novel 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. The results of the SAR studies in this series led to the identification of compound 28, which exhibited better MT(1) and MT(2) receptor affinities than melatonin itself. This work also established the benzoxazole nucleus as a melatoninergic pharmacophore, which served as an isosteric replacement to the previously established alkoxyaryl core.
Asunto(s)
Benzoxazoles/síntesis química , Benzoxazoles/metabolismo , Melatonina/química , Melatonina/fisiología , Receptores de Melatonina/fisiología , Diseño de Fármacos , Humanos , Ligandos , Melatonina/metabolismo , Unión ProteicaRESUMEN
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.
