RESUMEN
Ligand-based virtual screening with a 3D pharmacophore led to the discovery of 30 novel, diverse and drug-like ligands of the human cannabinoid receptor 1 (hCB(1)). The pharmacophore was validated with a hit rate of 16%, binding selectivity versus hCB(2), and expected functional profiles. The discovered compounds provide new tools for exploring cannabinoid pharmacology.
Asunto(s)
Química Farmacéutica/métodos , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Animales , Cannabinoides/química , Cannabis/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Ligandos , Ratones , Modelos Químicos , Estructura Molecular , Obesidad/tratamiento farmacológico , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/química , Receptor Cannabinoide CB2/química , RimonabantRESUMEN
Ligand-based virtual screening led to the discovery of a new class of potent inverse agonists of the human cannabinoid receptor 1, hCB(1), which are selective versus hCB(2). These CB(1) ligands present intriguing departures from a classical CB(1) antagonist pharmacophore. Elements of SAR are discussed in this context.
Asunto(s)
Cannabinoides/síntesis química , Cannabinoides/farmacología , Receptor Cannabinoide CB1/agonistas , Cannabinoides/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Ligandos , Estructura Molecular , Receptor Cannabinoide CB2/agonistas , Relación Estructura-ActividadRESUMEN
Recent reports suggest that elevated levels of plasminogen activator inhibitor (PAI)-1 may contribute to tumor progression. We have recently shown that antibodies to PAI-1 block the invasive and migratory potential of human fibrosarcoma cells and suppress angiogenesis in vitro. Here we report the in vitro evaluation of a low-molecular-weight modulator of PAI-1, XR5967, on invasion, migration and angiogenesis. XR5967, a diketopiperazine, dose-dependently inhibited the activity of human and murine PAI-1, towards urokinase plasminogen activator (uPA), with IC50 values of 800 nM and 8.3 microM, respectively. This was confirmed by SDS-PAGE, revealing that XR5967 inhibited complex formation between PAI-1 and uPA. This suppression may be caused by XR5967 promoting insertion of the reactive center loop within PAI-1. XR5967 dose-dependently inhibited the invasion of human HT1080 fibrosarcoma cells through Matrigel. Their invasion was reduced by 57% (p<0.001) at 5 microM. HT1080 cell migration was inhibited in a similar manner, indicating that PAI-1 may play an additional role in invasion, which is distinct to its role in the regulation of proteolysis. The potential of XR5967 to inhibit the invasion/migration of human endothelial cells was investigated in an in vitro model of angiogenesis. In this model XR5967 reduced tubule formation by 77% at 5 microM (p<0.001), highlighting a crucial role for PAI-1 in angiogenesis. These data stress the importance of a balanced proteolysis in the processes of invasion, migration and angiogenesis. Our results support the clinical findings and indicate that modulation of PAI-1 activity, with low-molecular-weight inhibitor of PAI-1 activity, may be of therapeutic benefit for the treatment of cancer.