RESUMEN
3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6ß-amidoepoxymorphinan group of opioids. We present the synthesis and pharmacological evaluation of five analogs of IBNtxA. The scaffold of IBNtxA was modified by removing the 14-hydroxy group, incorporating a 7,8 double bond and various N-17 alkyl substituents. The structural modifications resulted in analogs with picomolar affinities for opioid receptors. The lead compound (MP1104) was found to exhibit approximately 15-fold greater antinociceptive potency (ED50 = 0.33 mg/kg) compared with morphine, mediated through the activation of kappa- and delta-opioid receptors. Despite its kappa agonism, this lead derivative did not cause place aversion or preference in mice in a place-conditioning assay, even at doses 3 times the analgesic ED50. However, pretreatment with the lead compound prevented the reward behavior associated with cocaine in a conditioned place preference assay. Together, these results suggest the promise of dual acting kappa- and delta-opioid receptor agonists as analgesics and treatments for cocaine addiction.
Asunto(s)
Analgésicos Opioides/síntesis química , Analgésicos Opioides/farmacología , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Morfinanos/síntesis química , Morfinanos/farmacología , Analgésicos Opioides/química , Animales , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Trastornos Relacionados con Cocaína/metabolismo , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Evaluación Preclínica de Medicamentos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Estructura Molecular , Morfinanos/química , Naltrexona/análogos & derivados , Naltrexona/química , Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/farmacología , Distribución Aleatoria , Receptores Opioides delta/agonistas , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/genética , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Recompensa , Conducta Espacial/efectos de los fármacos , Conducta Espacial/fisiologíaRESUMEN
We report a novel approach to synthesize carfentanil amide analogues utilizing the isocyanide-based four-component Ugi multicomponent reaction. A small library of bis-amide analogues of carfentanil was created using N-alkylpiperidones, aniline, propionic acid, and various aliphatic isocyanides. Our lead compound showed high affinity for mu (MOR) and delta opioid receptors (DOR) with no appreciable affinity for kappa (KOR) receptors in radioligand binding assays. The compound was found to be a mixed MOR agonist/partial DOR agonist in [(35)S]GTPγS functional assays, and it showed moderate analgesic potency in vivo. The compound showed no visible signs of physical dependence or constipation in mice. In addition, it produced less respiratory depression than morphine. Most mixed MOR/DOR opioids reported in the literature are peptides and thereby systemically inactive. Our approach utilizing a multicomponent reaction has the promise to deliver potent and efficacious small-molecule analgesics with potential clinical utility.