RESUMO
As part of an ongoing drug development effort aimed at selective opioid receptor ligands based on the pawhuskin natural products we have synthesized a small set of amide isosteres. These amides were centered on lead compounds which are selective antagonists for the delta and kappa opioid receptors. The amide isomers revealed here show dramatically different activity from the parent stilbene compounds. Three of the isomers synthesized showed antagonist activity for the opioid growth factor (OGF)/opioid growth factor receptor (OGFR) axis which is involved in cellular and organ growth control. This cellular signaling mechanism is targeted by "low-dose" naltrexone therapy which is being tested clinically for multiple sclerosis, Crohn's disease, cancer, and wound healing disorders. The compounds described here are the first selective small molecule ligands for the OGF/OGFR system and will serve as important leads and probes for further study.
Assuntos
Amidas/farmacologia , Receptores Opioides/metabolismo , Amidas/síntese química , Amidas/química , Animais , Células COS , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Studies of directed ortho metalation reactions on an aromatic substrate with multiple potential directing groups have identified conditions that favor either of two regioisomers. One of these regioisomers has been converted to an analogue of the stilbene pawhuskin A, and been shown to have high selectivity as an antagonist of the delta opioid receptor. Docking studies have suggested that this compound can adopt a conformation similar to naltrindole, a known delta antagonist.
Assuntos
Antagonistas de Entorpecentes/química , Receptores Opioides delta/antagonistas & inibidores , Estilbenos/química , Terpenos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Antagonistas de Entorpecentes/síntese química , Estilbenos/síntese química , Estilbenos/farmacologia , Terpenos/síntese química , Terpenos/farmacologiaRESUMO
The natural stilbene pawhuskin A has been shown to function as an opioid receptor antagonist, with preferential binding to the κ receptor. This finding encouraged assembly of a set of analogues to probe the importance of key structural features. Assays on these compounds determined that one (compound 29) shows potent opioid receptor binding activity and significantly improved selectivity for the κ receptor. These studies begin to illuminate the structural features of these non-nitrogenous opioid receptor antagonists that are required for activity.
