Opiate receptor interaction of compounds derived from or structurally related to fentanyl

Abstract

The opiate receptor affinity of compounds derived from or structurally related to fentanyl (1) was determined by in vitro receptor binding assays. The relatively high affinity of fentanyl (3 times morphine) was hardly influenced by the introduction of a 2-CH3, 2-OCH3, or a 2-Cl substituent into the anilino phenyl and was moderately reduced by 2-C2H5, 2-OC2H5, and 2,6-(CH3)2 substitution in this ring. Removal of the n-propionyl g in vitro receptor binding assays. The relatively high affinity of fentanyl (3 times morphine) was hardly influenced by the introduction of a 2-CH3, 2-OCH3, or a 2-Cl substituent into the anilino phenyl and was moderately reduced by 2-C2H5, 2-OC2H5, and 2,6-(CH3)2 substitution in this ring. Removal of the n-propionyl g in vitro receptor binding assays. The relatively high affinity of fentanyl (3 times morphine) was hardly influenced by the introduction of a 2-CH3, 2-OCH3, or a 2-Cl substituent into the anilino phenyl and was moderately reduced by 2-C2H5, 2-OC2H5, and 2,6-(CH3)2 substitution in this ring. Removal of the n-propionyl group of the 2-OCH3 derivative, fixation of the anilino phenyl in fentanyl to the propionyl group or the piperidine ring, and replacement of the amide N by C all caused a sharp decline of receptor affinity. Examination of molecular models seemed to indicate that optimal opiate receptor interaction of fentanyl and its derivatives requires a virtually perpendicular position of the anilino phenyl with respect to the amide function.