RESUMEN
Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.
Asunto(s)
Analgésicos/administración & dosificación , Benzamidas/administración & dosificación , Benzopiranos/administración & dosificación , Dolor/tratamiento farmacológico , Receptores Opioides delta/agonistas , Administración Oral , Analgésicos/síntesis química , Analgésicos/química , Animales , Benzamidas/síntesis química , Benzamidas/química , Benzopiranos/síntesis química , Benzopiranos/química , Disponibilidad Biológica , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Humanos , Dosis Máxima Tolerada , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Ratas , Pruebas de ToxicidadRESUMEN
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
Nitric oxide generated by the nitric oxide synthase (NOS) isoforms contributes to pain processing. The selective inhibition of iNOS might represent a novel, therapeutic target for the development of antinociceptive compounds. However, few isoform-selective inhibitors of NOS have been developed. The present experiments examined the anti-inflammatory and antinociceptive activity of a selective inducible nitric oxide (iNOS) inhibitor, AR-C102222, on arachidonic acid-induced ear inflammation, Freund's complete adjuvant (FCA)-induced hyperalgesia, acetic acid-induced writhing, and tactile allodynia produced by L5 spinal nerve ligation (L5 SNL) or hindpaw incision (INC). AR-C102222 at a dose of 100mg/kg p.o., significantly reduced inflammation produced by the application of arachidonic acid to the ear, attenuated FCA-induced mechanical hyperalgesia, and attenuated acetic acid-induced writhing. In the L5 SNL and INC surgical procedures, tactile allodynia produced by both procedures was significantly reduced by 30mg/kg i.p. of AR-C102222. These data demonstrate that the selective inhibition of iNOS produces antinociception in different models of pain and suggest that the iNOS-NO system plays a role in pain processing.
Asunto(s)
Hiperalgesia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Mononeuropatías/tratamiento farmacológico , Óxido Nítrico Sintasa/antagonistas & inhibidores , Dolor/tratamiento farmacológico , Quinazolinas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Inflamación/complicaciones , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Mononeuropatías/complicaciones , Dolor/etiología , Ratas , Ratas Sprague-DawleyRESUMEN
A series of 3-substituted analogs (3) of the parent kappa agonist, 1, were prepared to limit access to the central nervous system. With the exception of compound 3j, all other compounds bound to the human kappa opioid receptor with high affinity (K(i)=0.31-9.5 nM) and were selective for kappa over mu and delta opioid receptors. Compounds 3c, d, and 3g-i produced potent antinociceptive activity in the rat formalin assay (i.paw) and the mouse acetic acid-induced writhing assay (s.c.), with weak activity in the mouse platform sedation test. The peripheral restriction indices of 3c, d, 3g, and 3i were improved 2- to 7-fold compared to the parent compound 1, and these compounds were approximately 2- to 5-fold more potent than the peripheral kappa agonist ICI 204448.