ABSTRACT
The α-iminoamide derivative, 4b was designed and synthesized as a novel agonist selective for the opioid κ receptor. The amide was constrained to an orientation horizontal to the F-ring of the azabicyclo[2.2.2]octane skeleton, which remarkably improved its affinity, selectivity, and agonistic activity for the κ receptor. This finding was newly established by chemical modification of the nitrogen atom at the 8-position in the azabicyclo[2.2.2]octane skeleton. This modification would never have been found with KNT-63, a derivation of oxabicyclo[2.2.2]octane. These results may provide valuable information for the future development of novel κ selective agonists.
Subject(s)
Amides/chemistry , Aza Compounds/pharmacology , Bridged Bicyclo Compounds/pharmacology , Drug Design , Receptors, Opioid, kappa/agonists , Aza Compounds/chemistry , Bridged Bicyclo Compounds/chemistry , Humans , Molecular Conformation , Molecular Structure , Protein Binding , Structure-Activity RelationshipABSTRACT
Several derivatives with an azabicyclo[2.2.2]octane skeleton having a 7-amide side chain were synthesized. Compounds that had an electron-donating group exhibited high affinity for the µ opioid receptor while those with a bulky substituent at the 8-nitrogen atom had low affinities for all receptor types. High affinities and selectivities for the κ receptor resulted from the introduction of the longer amide side chain at the 7α-position. Our studies indicate that the orientation of the amide side chain at the 7-position within the azabicyclo[2.2.2]octane skeleton is related to selectivity for the κ receptor.
Subject(s)
Amides/chemical synthesis , Analgesics, Opioid/chemical synthesis , Azabicyclo Compounds/chemical synthesis , Receptors, Opioid, delta/chemistry , Receptors, Opioid, kappa/chemistry , Receptors, Opioid, mu/chemistry , Amides/chemistry , Analgesics, Opioid/chemistry , Azabicyclo Compounds/chemistry , Biological Assay , Drug Design , Humans , Ligands , Receptors, Opioid, delta/agonists , Receptors, Opioid, kappa/agonists , Receptors, Opioid, mu/agonists , Sensitivity and Specificity , Structure-Activity RelationshipABSTRACT
A novel opioid ligand possessing a stable and cyclic imine 16 and its derivatives with an azabicyclo[2.2.2]octane skeleton were synthesized. The imine 16 showed higher affinity for the µ receptor than compound 21 with an oxabicyclo[2.2.2]octane skeleton. Azabicyclo[2.2.2]octane derivative 18d with a cyclopropylmethyl group on the 8-nitrogen showed the highest affinity for the µ receptor among the synthesized derivatives.
