Synthesis and stereochemistry of 7-phenyl-2-propionanilidobenzo[a]quinolizidine derivatives. Structural probes of fentanyl analgesics.
The for diastereomers of N-(1,3,4,6,7,11b-hexahydro-7-phenyl-2H-benzo[a]quinolizin-2-yl)-N-phenylpropanamide (7c, 7d, 9c, and 9d), which are conformationally restricted analogues of fentanyl, were synthesized and separately 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 2 alpha isomers (7d and 9d) exist in solution as mixtures of cis- and trans-fused conformers with ca. 90 and 45% 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. 0.5% of fentanyl and 2% of morphine). The analgesic activity of 7d was abolished by the opiate antagonist naloxone.
D000700:Analgesics; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship
D000700:Analgesics; D011957:Receptors, Opioid; D005283:Fentanyl