Design and synthesis of novel opioid ligands with an azabicyclo[2.2.2]octane skeleton having a 7-amide side chain and their pharmacologies

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.