RESUMEN
Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB(2) receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB(2) receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects.
Asunto(s)
Benzamidas/uso terapéutico , Neuralgia/tratamiento farmacológico , Receptor Cannabinoide CB2/metabolismo , Sulfonamidas/uso terapéutico , Animales , Benzamidas/síntesis química , Benzamidas/farmacología , Sitios de Unión , Relación Dosis-Respuesta a Droga , Ligandos , Ratones , Modelos Animales , Modelos Químicos , Dimensión del Dolor/efectos de los fármacos , Ratas , Receptor Cannabinoide CB2/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacologíaRESUMEN
A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, mu opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective mu opioid receptor antagonist, which interacts selectively with mu peripheral receptors.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Piperidinas/química , Piperidinas/farmacología , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides mu/antagonistas & inhibidores , Administración Oral , Animales , Membrana Celular/metabolismo , Cromatografía Líquida de Alta Presión , Diprenorfina/metabolismo , Tránsito Gastrointestinal/efectos de los fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Loperamida/farmacología , Ratones , Estructura Molecular , Piperidinas/síntesis química , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of malonamide derivatives was synthesized. These amides were shown to be potent and selective kappa opioid receptor agonists.
Asunto(s)
Química Farmacéutica/métodos , Malonatos/síntesis química , Malonatos/farmacología , Receptores Opioides kappa/antagonistas & inhibidores , Citocromo P-450 CYP2D6/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Cinética , Malonatos/química , Modelos Químicos , Conformación MolecularRESUMEN
A novel series of phenylamino acetamide derivatives was synthesized. These amides were shown to be potent and selective kappa opioid receptor agonists.
Asunto(s)
Acetamidas/química , Analgésicos Opioides/química , Compuestos de Anilina/química , Receptores Opioides kappa/agonistas , Analgésicos Opioides/farmacología , Animales , Humanos , Relación Estructura-ActividadRESUMEN
Two novel chemical classes of kappa opioid receptor agonists, chroman-2-carboxamide derivatives and 2,3-dihydrobenzofuran-2-carboxamide derivatives, were synthesized. These agents exhibited high and selective affinity for the kappa opioid receptor.
