RESUMEN
The modulation of melatonin signaling in peripheral tissues holds promise for treating metabolic diseases like obesity, diabetes, and nonalcoholic steatohepatitis. Here, several benzimidazole derivatives have been identified as novel agonists of the melatonin receptors MT1 and MT2. The lead compounds 10b, 15a, and 19a demonstrated subnanomolar potency at MT1/MT2 receptors, high oral bioavailability in rodents, peripherally preferred exposure, and excellent selectivity in a broad panel of targets. Two-month oral administration of 10b in high-fat diet rats led to a reduction in body weight gain similar to dapagliflozin with superior results on hepatic steatosis and triglyceride levels. An early toxicological assessment indicated that 10b (also codified as ACH-000143) was devoid of hERG binding, genotoxicity, and behavioral alterations at doses up to 100 mg/kg p.o., supporting further investigation of this compound as a drug candidate.
Asunto(s)
Acetamidas/uso terapéutico , Fármacos Antiobesidad/uso terapéutico , Bencimidazoles/uso terapéutico , Hígado Graso/tratamiento farmacológico , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT2/agonistas , Acetamidas/síntesis química , Acetamidas/farmacocinética , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacocinética , Compuestos de Bencidrilo/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Dieta Alta en Grasa , Diseño de Fármacos , Hígado Graso/patología , Glucósidos/farmacología , Hígado/patología , Masculino , Ratones , Estructura Molecular , Obesidad/tratamiento farmacológico , Ratas Sprague-Dawley , Ratas Wistar , Relación Estructura-Actividad , Triglicéridos/metabolismoRESUMEN
There has been a search for more effective and safe hypnotic drugs in the last decades. Zolpidem, zaleplon, zopiclone, eszopiclone (the z-drugs) and indiplon are GABA-A modulators which bind selectively α1 subunits, thus, exhibiting similar mechanisms of action, although recent evidence suggests that eszopiclone is not as selective for α1 subunit as zolpidem is. Ramelteon and tasimelteon are new chrono-hypnotic agents, selective for melatonin MT1 and MT2 receptors. On the other hand, the consumption of sedative antidepressant drugs is significantly increasing for the treatment of insomnia, in the last years. As an experimental drug, eplivanserin is being tested as a potent antagonist of serotonin 2-A receptors (ASTAR) with a potential use in sleep maintenance difficulty. Another recent pharmacological agent for insomnia is almorexant, which new mechanism of action involves antagonism of hypocretinergic system, thus inducing sleep. Finally we also discuss the potential role of other gabaergic drugs for insomnia.
Asunto(s)
Antidepresivos/uso terapéutico , Agonistas del GABA/uso terapéutico , Hipnóticos y Sedantes/uso terapéutico , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT2/agonistas , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , HumanosRESUMEN
During vertebrate neurodevelopment, neuritogenesis and synaptogenesis are modulated by intracellular cAMP rises. Melatonin, which is implicated in neuronal differentiation, mainly inhibits this pathway. Here, an investigation about the profile of this effect during the vertebrate neurodevelopment is reported. In the embryonic chick retinas at days 8, 12, 14, 16 and at 2 days post-hatched (E8, E12, E14, E16 and PH), those control embryonic retinas incubated only with the phosphodiesterase inhibitor at days corresponding to commencement of neuronal differentiation (E8, E12) and PH, presented cAMP levels inhibited by melatonin. While the cAMP accumulation stimulated by forskolin was inhibited in the embryonic retinas at all testing days. Neither the unselective antagonist N-acetyl-2-benziltryptamine (luzindole) nor the selective Mel(1b) antagonist 4-phenyl-2-propionamidotetralin (4-P-PDOT) blocked the melatonin concentration-dependent inhibitory effect on cAMP accumulation in the retinas initiating differentiation (E7-E9), suggesting a tight binding between melatonin and their receptors. However, 4-P-PDOT competitively reverted the melatonin effect on cAMP stimulated by forskolin during synaptogenesis stages. Together, the melatonin effect on cAMP levels in chick retina, which is mainly through melatonin receptors, is depending on the developmental period observed, probably taking part in the mechanisms surrounding the melatonin action on neuronal differentiation.
Asunto(s)
Diferenciación Celular/fisiología , AMP Cíclico/metabolismo , Melatonina/fisiología , Neuronas/metabolismo , Retina/embriología , Retina/metabolismo , Animales , Unión Competitiva/efectos de los fármacos , Unión Competitiva/fisiología , Diferenciación Celular/efectos de los fármacos , Embrión de Pollo , Colforsina/farmacología , AMP Cíclico/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Melatonina/farmacología , Neuronas/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Receptor de Melatonina MT2/agonistas , Receptor de Melatonina MT2/antagonistas & inhibidores , Receptor de Melatonina MT2/metabolismo , Retina/efectos de los fármacos , Tetrahidronaftalenos/farmacología , Triptaminas/farmacologíaRESUMEN
The antiallodynic effect of melatonin after intrathecal (it) and oral administration as well as the possible participation of MT(2) and opioid receptors in melatonin-induced antiallodynia in neuropathic rats were assessed. Ligation of the L5/L6 spinal nerves produced a clear-cut tactile allodynia in the rats. Intrathecal (3-100 microg) and oral (37.5-300 mg/kg) administration of melatonin decreased tactile allodynia induced by spinal nerve ligation. Intrathecal administration of the preferential MT(2) receptor antagonist luzindole (1-100 microg), but not vehicle, significantly diminished in a dose-dependent manner the antiallodynic effect induced by melatonin (100 microg, it). Oral (0.01-1mg/kg) or intrathecal (0.1-10 microg) administration of the highly selective MT(2) receptor antagonist 4P-PDOT diminished the antiallodynic activity induced by oral (150 mg/kg) or intrathecal (100 microg) administration of melatonin, respectively. Subcutaneous (1mg/kg) or intrathecal (0.5-50 microg) treatment with naltrexone, but not vehicle, significantly diminished the antiallodynic effect induced by oral (150 mg/kg) or intrathecal (100 microg) administration of melatonin. Oral melatonin (150 mg/kg)-induced antiallodynia was partially reduced by the spinal administration of 4P-PDOT (10 microg). Moreover, the spinal effect of melatonin (100 microg) was significantly reduced by the combination 4P-PDOT (0.1 microg)-naltrexone (0.5 microg). At the greatest tested doses, the antagonist drugs did not modify tactile allodynia in neuropathic rats. Melatonin (100 microg or 300 mg/kg) did not affect motor co-ordination in the rotarod test. Results indicate that melatonin reduces tactile allodynia in neuropathic rats after intrathecal and oral administration. Moreover, data suggest the participation of spinal MT(2) and opioid receptors in the melatonin-induced antiallodynic effect in this model.
Asunto(s)
Melatonina/administración & dosificación , Dolor/tratamiento farmacológico , Dolor/metabolismo , Receptor de Melatonina MT2/metabolismo , Receptores Opioides/metabolismo , Administración Oral , Animales , Femenino , Inyecciones Espinales , Dolor/fisiopatología , Estimulación Física/métodos , Ratas , Ratas Wistar , Receptor de Melatonina MT2/agonistas , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Tacto/efectos de los fármacos , Tacto/fisiologíaRESUMEN
Systemically administered melatonin has been reported to produce antinociception and to inhibit spinal nociceptive transmission in rats. The present study was designed to investigate in anesthetized rats (i) whether intrathecally administered melatonin can depress synaptic potentiation (wind-up) in the spinal cord, and (ii) whether this effect is prevented by intrathecal (i.t.) administration of the MT2 receptor antagonist luzindole. Results showed that melatonin i.t. (10, 30 and 90 microg) induced dose-dependent inhibition of wind-up activity (ED50=52.06 microg i.t.), an effect that was prevented by 100 microg i.t. of luzindole. Since wind-up is dependent on NMDA receptor activation, the results suggest that melatonin can interfere with the NMDA-mediated glutamatergic component of pain transmission in rat spinal cord by acting on MT2 receptors.