ABSTRACT
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.
Subject(s)
Receptors, Opioid/agonists , Small Molecule Libraries/chemistry , Spiro Compounds/chemistry , Animals , Anxiety/drug therapy , Disease Models, Animal , Motor Activity/drug effects , Opioid Peptides/chemistry , Opioid Peptides/metabolism , Protein Binding , Rats , Receptors, Opioid/metabolism , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Spiro Compounds/pharmacology , Spiro Compounds/therapeutic use , Structure-Activity Relationship , Nociceptin Receptor , NociceptinABSTRACT
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.
