RESUMO
Small molecule mu agonists based on the 4-phenyl piperidine scaffold were designed and synthesized to further investigate the therapeutic potential of loperamide analogs. The resulting compounds show excellent agonistic activity towards the human mu receptor with interesting SAR trends within the series.
Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Receptores Opioides mu/agonistas , Linhagem Celular , Humanos , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 1,3-dihydro-2,1,3-benzothiadiazol-2,2-diones (I) and 3,4-dihydro-1H-2,1,3-benzothidiazin-2,2-diones (II) were prepared. While the five-member ring series (I) did not show good affinity for opioid receptors, the six-member ring series (II) exhibited extremely high affinity and selectivity for the NOP receptor and showed full agonist activity, as determined by stimulation of GTPgamma[35S] binding.
Assuntos
Receptores Opioides mu/agonistas , Tiazinas/síntese química , Tiazóis/síntese química , Animais , Humanos , Técnicas In Vitro , Ligantes , Ensaio Radioligante , Ratos , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade , Tiazinas/química , Tiazinas/farmacologia , Tiazóis/química , Tiazóis/farmacologiaRESUMO
Based on literature structures, we proposed a pharmacophore for NOP receptor ligands and used it as a guide for the design of a focused piperidine library and an optimization library. Potent NOP receptor agonists and antagonists were obtained from these libraries as well as a few potent, mu selective agonists.