Privileged Structure-Based Design, Synthesis And Biological Evaluations Of κ Opioid Ligands

Current progress in the development of classical κ opioid agonists (e.g., morphinans, arylacetamides, diterpenes and other structures) were firstly reviewed based on their specific characteristics of binding, potency and efficacy in this dissertation. Relevant SAR (Structure-Activity Relationships) analyses were also conducted.With LQ004C, a member of κ opioids derived from morphinans, as the leading compound, a series of compounds were designed and synthesized based on both classical medicinal chemistry methods and latest molecular modeling approaches. Moreover, functional groups with electric, steric, basic, hydrogen bond donor/acceptor features were introduced to the unique 4-amino substitution site of the leading compound to investigate the effects of these factors on the binding and subtype selectivity of compound candidates.27 target compounds were designed, synthesized and evaluated for their binding affinities to μ,δ, and κ opioid receptor. The results from the studies has identified new potent and selective κ ligand, SLL-039 with a Ki value of 0.5 nM at the κ receptor and 300-and 600-fold selectivity relative to the μ and δ receptors, further functional assay showed that it was a κ agonist with a EC50 value of 2.0 nM, which may become a potential κ ligand.