RESUMEN
Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical δ, µ and κ opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented.
Asunto(s)
Receptores Opioides/agonistas , Bibliotecas de Moléculas Pequeñas/química , Compuestos de Espiro/química , Animales , Ansiedad/tratamiento farmacológico , Modelos Animales de Enfermedad , Actividad Motora/efectos de los fármacos , Péptidos Opioides/química , Péptidos Opioides/metabolismo , Unión Proteica , Ratas , Receptores Opioides/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Relación Estructura-Actividad , Receptor de Nociceptina , NociceptinaRESUMEN
The first example of one-pot sequential Cope/Rauhut-Currier reactions are reported and used to make functionalized decalin structures with all-carbon quaternary stereocenters. The substrates for the new sequential reaction are generated through a six-step sequence including an enantioselective Birch reduction-allylation reaction which makes the overall process asymmetric.