RESUMO
3-Azabicyclo[3.1.0]hexane compounds were designed as novel achiral µ opioid receptor ligands for the treatment of pruritus in dogs. In this paper, we describe the SAR of this class of opioid ligand, highlighting changes to the lead structure which led to compounds having picomolar binding affinity, selective for the µ receptor over δ and κ subtypes. Some subtleties of functional activity will also be described.
Assuntos
Antipruriginosos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Hexanos/síntese química , Prurido/tratamento farmacológico , Receptores Opioides mu/antagonistas & inibidores , Animais , Antipruriginosos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cães , Cobaias , Hexanos/farmacologia , Humanos , Técnicas In Vitro , Cinética , Ligantes , Prurido/metabolismo , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-AtividadeRESUMO
The structure of the unusual anthelmintic pyrrolobenzoxazine terpenoid natural product CJ-12662 was established by X-ray crystallography and partial synthesis from 2-chloronitrobenzene. An unusual Meisenheimer-type rearrangement was used to provide the core pyrrolobenzoxazine heterocycle, and coupling of a tetracyclic pyrrolobenzoxazine lactone with the terpene alcohol was used to complete the synthesis of CJ-12662.