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.

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Klein P, Nelson WL

J Med Chem. 1992 Nov 27;35(24):4589-94.

PubMed ID

1335078 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Diprenorphine	Kappa-type opioid receptor	IC 50 (nM)	1.8	N/A	N/A	Details
Diprenorphine	Mu-type opioid receptor	IC 50 (nM)	0.71	N/A	N/A	Details
Naloxone	Kappa-type opioid receptor	IC 50 (nM)	50	N/A	N/A	Details
Naloxone	Mu-type opioid receptor	IC 50 (nM)	8.9	N/A	N/A	Details
Oxymorphone	Mu-type opioid receptor	IC 50 (nM)	1.4	N/A	N/A	Details