The potent opioid agonist, (+)-cis-3-methylfentanyl binds pseudoirreversibly to the opioid receptor complex in vitro and in vivo: evidence for a novel mechanism of action.
The present study demonstrates that pretreatment of rat brain membranes with (+)-cis-3-methylfentanyl [(+)-cis-MF], followed by extensive washing of the membranes, produces a wash-resistant decrease in the binding of [3H]-[D-ala2,D-leu5]enkephalin to the d binding site of the opioid receptor complex (delta cx binding site). Intravenous administration of (+)-cis-MF (50 micrograms/kg) to rats produced a pronounced catalepsy and also produced a wash-resistant masking of delta cx and mu binding sites in membranes prepared 120 min post-injection. Administration of 1 mg/kg i.v. of the opioid antagonist, 6-desoxy-6 beta-fluoronaltrexone (cycloFOXY), 100 min after the injection of (+)-cis-MF (20 min prior to the preparation of membranes) completely reversed the catatonia and restored masked delta cx binding sites to control levels. This was not observed with (+)-cycloFOXY. The implications of these and other findings for the mechanism of action of (+)-cis-MF and models of the opioid receptors are discussed.
Band
L
L
Laboratory of Medicinal Chemistry, NIDDK, Bethesda, MD 20892.
Xu
H
H
Bykov
V
V
Greig
N
N
Kim
C H
CH
Newman
A
A
Jacobson
A E
AE
Rice
K C
KC
Rothman
R B
RB
D000818:Animals; D001921:Brain / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D002389:Catatonia / Q000139:chemically induced; D002462:Cell Membrane / Q000187:drug effects; D016308:Enkephalin, Leucine-2-Alanine / Q000378:metabolism; D005283:Fentanyl / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D009292:Narcotic Antagonists; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta
D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D016308:Enkephalin, Leucine-2-Alanine; C030592:3-methylfentanyl; D005283:Fentanyl