Synthesis and Stereochemistry of 7-Phenyl-2-propionanilidobenzoquinolizidine Derivatives. Structural Probes of Fentanyl Analgesics

Article abstract of DOI:10.1021/jm00133a017

The four diastereomers of N-(1,3,4,6,7,11b-hexahydro-7-phenyl-2H-benzoquinolizin-2-yl)-N-phenylpropanamide (7c, 7d, 9c, and 9d), which are conformationally restricted analogues of fentanyl, were synthesized and seperately tested for analgesic activity and affinity for the opiate receptor of rat brain.Stereochemical assignments for 7c, 7d, 9c, and 9d were deduced from NMR spectral analyses.Conformational analysis revealed that the 2α isomers (7d and 9d) exist in solution as mixtures of cis- and trans-fused conformers with ca. 90 and 45percent cis form, respectively.Other compounds (12a, 12b, and 14) related to these propionanilides were also prepared, stereochemically characterized, and tested.Weak analgesic activity was observed for 7d, and both 7d and 9d bound to the opiate receptor with an I50 of ca. 1100 and 1500 nM, respectively (ca. 0.5percent of fentanyl and 2percent of morphine).The analgesic activity of 7d was abolished by the opiate antagonist naloxone.