O3-(2-carbomethoxyallyl) ethers of opioid ligands derived from oxymorphone, naltrexone, etorphine, diprenorphine, norbinaltorphimine, and naltrindole. Unexpected O3-dealkylation in the opioid radioligand displacement assay.
O3-(2-Carbomethoxyallyl) ether derivatives of some phenolic 4,5-epoxymorphinan opioid ligands have been prepared in a simple one-step procedure, and their behavior in the radioligand receptor assay was compared to their phenolic precursors. These O3-ether ligands appeared to show significant affinity for opioid receptors, about 2-fold less than the parent phenols, and their receptor selectivities were similar. However, on close examination of the stability of a representative ether 2b in the radioligand displacement assay, considerable O3-dealkylation was observed. The dealkylation process occurred even after denaturation of the proteins of the membrane preparation, and it occurred in the presence of model nucleophiles imidazole and thiophenol. Thus, what apparently was unusual activity is explained by O3-dealkylation to the parent phenol (e.g., 2a). Saturated ether analog 2c was not dealkylated under the conditions of the radioligand displacement assay and was a very weak opioid ligand. We conclude that the conversion of the O3(2-carbomethoxyallyl) ether electrophilic ligands to their parent phenols accounts for their activity in the opioid radioligand displacement assay.
Klein
P
P
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Nelson
W L
WL
D000478:Alkylation; D000818:Animals; D001921:Brain / Q000378:metabolism; D004174:Diprenorphine / Q000031:analogs & derivatives; D004355:Drug Stability; D004987:Ethers / Q000138:chemical synthesis* / Q000378:metabolism; D005048:Etorphine / Q000031:analogs & derivatives; D006168:Guinea Pigs; D007211:Indoles / Q000737:chemistry; D008689:Methacrylates / Q000138:chemical synthesis* / Q000378:metabolism; D015394:Molecular Structure; D009019:Morphinans / Q000737:chemistry; D009271:Naltrexone / Q000031:analogs & derivatives / Q000737:chemistry; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000378:metabolism; D009294:Narcotics / Q000138:chemical synthesis* / Q000378:metabolism; D010111:Oxymorphone / Q000031:analogs & derivatives; D010636:Phenols / Q000378:metabolism; D011869:Radioligand Assay; D011957:Receptors, Opioid / Q000378:metabolism*; D014316:Tritium
D004987:Ethers; D007211:Indoles; D008689:Methacrylates; D009019:Morphinans; D009292:Narcotic Antagonists; D009294:Narcotics; D010636:Phenols; D011957:Receptors, Opioid; D014316:Tritium; D004174:Diprenorphine; C051844:norbinaltorphimine; D005048:Etorphine; D009271:Naltrexone; D010111:Oxymorphone; C055382:naltrindole