[Synthesis, analgesic activity and structure-activity relationship of 4-N-propionyl analogs of cis-3-methyl fentanyl].

The synthesis of some 4-N-propionyl analogs of cis-3-methyl fentanyl by acyl chloride method. anhydride method, mixed anhydride method and DCC method is reported. The ethyl group in 4-N-propionyl portion of cis-3-methyl fentanyl was substituted by some groups with different electronic property. In mouse hot plate test, all compounds showed typical morphine-like action with analgesic potency corresponding to 49-1963 times that of morphine. Compound 3 was found to exhibit higher analgesic activity than cis-3-methyl fentanyl. Semiempirical INDO calculations have been undertaken for 4 typical compounds and it was found that as a result of introduction of chlorovinyl, compound 3 exhibited characteristics of electronic structure different from that of cis-3-methyl fentanyl. The relationships between analgesic activity and the electronic structure of these compounds were discussed.