Studies on synthesis and relationship between analgesic activity and receptor affinity for 3-methyl fentanyl derivatives.

In the present paper, the synthesis and analgesic activity (mice, i.p. hot plate test) of the derivatives of 3-methyl fentanyl are briefly described. Compound 7302, cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropionamide (cis: 3-methyl/4-N-phenylpropionamide) is found to be the most potent analgesic agent in this series synthesized by our laboratory (ED50 = 0.0022 mg/kg). The analgesic activity of 7302 is 28 times more potent than that of fentanyl and 6300 times more than that of morphine. The partition coefficients of 10 compounds in the series are determined by high performance liquid chromatography (HPLC) and their log p values are about 3. There are no regular relationships between the analgesic activity and partition coefficients. Study on the specific binding of 8 out of the above 10 compounds to crude synaptic plasma membrane (P2-fraction) of mouse brain demonstrates that there is an excellent statistical linear correlation (r = 0.998) between the analgesic potency and the specific binding affinity. The result shows that the analgesic potency of the derivatives of this series is mainly dependent on binding affinity for opiate receptor.