RESUMEN
Novel double-capped triplet drugs, which have one pharmacophore unit and two epoxymethano or dimethylepoxymethano structures (termed cap or diMe-cap structures, respectively) were synthesized. Key intermediate oxazoline 16 derived from acetone enabled the effective synthesis of double-capped triplets. SYK-134 (7a) and SYK-135 (8a) with N-cyclopropylmethyl substituent and cap structures showed selectivities for the κ opioid receptor. On the other hand, the N-Me series exhibited selectivities for the µ opioid receptor. The double-capped triplet drugs with diMe-cap structures preferred the µ receptor independently of their N-substituents. SYK-385 (19b), one of the µ-selective double-capped triplet drugs, showed the highest selectivity for the µ receptor among the reported µ-selective nonpeptide ligands.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Metano/química , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Cobayas , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Metano/análogos & derivados , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
An improved synthetic method for triplet drugs with the 1,3,5-trioxazatriquinane skeleton was developed that used p-toluenesulfonylmethyl isocyanide (TosMIC) instead of 1,3-dithiane. Using the improved method, we synthesized compounds with two identical pharmacophore units and an epoxymethano group, that is, capped homotriplets. Among the synthesized capped homotriplets, KNT-123 showed high selectivity for the µ receptor over the κ receptor, and the µ selectivity was the highest among the reported µ selective nonpeptide ligands. KNT-123 administered subcutaneously induced a dose-dependent analgesic effect in the acetic acid writhing assay, and its potency was 11-fold more potent than that of morphine. KNT-123 may serve as a useful tool for the study of the pharmacological actions mediated specifically via the µ receptor.