RESUMEN
We have investigated a series of phenolic diaryl amino piperidine delta opioid receptor agonists, establishing the importance of the phenol functional group and substitution on the piperdine nitrogen for delta agonist activity and selectivity versus the mu and kappa opioid receptors. This study uncovered compounds with improved agonist potency and selectivity compared to the standard, non-peptidic delta agonist SNC-80. In vivo anti-nociceptive activity of analog 8e in two rodent models is discussed, demonstrating the potential of delta agonists to provide a novel mechanism for pain relief.
Asunto(s)
Analgésicos/química , Benzamidas/química , Difenilamina/análogos & derivados , Piperidinas/química , Receptores Opioides delta/agonistas , Analgésicos/síntesis química , Analgésicos/farmacología , Animales , Benzamidas/síntesis química , Benzamidas/farmacología , Difenilamina/síntesis química , Difenilamina/química , Difenilamina/farmacología , Modelos Animales de Enfermedad , Ratones , Piperidinas/síntesis química , Piperidinas/farmacología , Ratas , Receptores Opioides delta/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 1-aminotetralin scaffolds was synthesized via metal-catalyzed ring-opening reactions of heterobicyclic alkenes. Small libraries of amides and amines were made using the amino group of each scaffold as a handle. Screening of these libraries against human opioid receptors led to the identification of (S)-(S)-5.2a as a high-affinity selective mu ligand (IC(50)mu=5 nM, kappa=707 nM, delta=3,795 nM) displaying mu-agonist/antagonist properties due to its partial agonism (EC(50)=2.6 microM; E(max)=18%).