[Studies on structure-activity relationships and receptor binding feature for 3-methylfentanyl derivatives].
Ohmefentanyl is not only a potent analgesic agent, but also a selective ligand for mu opioid receptor. In order to search for more potent analgesics, more selective ligands and long duration of analgesic action in 3-methylfentanyl derivatives, we made modifications of the 1-phenethyl and 4-N-propionyl groups in 3-methylfentanyl and synthesized 15 new compounds. The analgesic activity, duration of analgesic action, receptor binding affinity and opioid sub-receptor selectivity of some of these compounds were measured. Primary pharmacological results showed that most of the compounds in this series possessed morphine-like effects. The analgesic activities of them were about 2-180 times more potent than that of morphine. The duration of analgesic action of the tested compounds was 6-10 times longer than that of fentanyl. The receptor binding affinities (IC50) of compounds 1-4 were 10(-7)-10(-8) mol. Compound 13 displayed the best binding selectivity on mu opioid receptor site with ratio mu/delta greater than 700 in rat brain membrane and mu/delta = 1000 in mouse brain membrane. The new compound may be proposed as a useful tool in studying the opioid receptor. According to the result of equations in reference 11, compounds 7-14 were designed and prepared. The observed log 1/c values of them were much closer to the calculated values.
Weng
J H
JH
Shanghai Institute of Materia Medica, Academia Sinica.
Xu
X R
XR
Zhu
Y C
YC
Zhou
J
J
Xu
H
H
Chi
Z Q
ZQ
D000700:Analgesics / Q000138:chemical synthesis*; D000818:Animals; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D017450:Receptors, Opioid, mu; D013329:Structure-Activity Relationship
D000700:Analgesics; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C030592:3-methylfentanyl; D005283:Fentanyl