κ Opioid Receptor Selective Affinity Labels: Electrophilic Benzeneacetamides as κ Selective Opioid Antagonists

An Chih Chang, Akira E. Takemori, William H. Ojala, William B. Gleason, Philip S. Portoghese

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

2-(3,4-Dichlorophenyl)-N-methyl-N-[1-(3- or 4-substituted phenyl)-2-(1-pyrrolidinyl)ethyl]-acetamides 3–6 were synthesized as κ-selective affinity labels and evaluated for opioid activity. In smooth muscle preparations, the non-electrophilic parent compound (+)-S-2 and the affinity labels 3–6 behaved as κ agonists in that they were potently antagonized by norbinaltorphimine (norBNI). In addition to the high binding affinity and selectivity of the 3-isothiocyanate 3 (DIPPA) to κ opioid receptors, wash studies have suggested that this involves covalent binding. In the mouse tail-flick assay, the 3- and 4-substituted isomers (3 and 5, respectively) produced long-lasting antagonism of the antinociceptive effect of the κ opioid agonist, (±)-trans-2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]acetamide ((±)-U50,488). In contrast, the non-electrophilic parent compound (+)-S-2 and the fumaramate derivative 4 were devoid of antagonist activity in the tail-flick assay. At substantially different doses, DIPPA (3) and the 4-isothiocyanate 5 also produced antinociception in the mouse abdominal stretch assay. In addition, DIPPA and the 3-fumaramate methyl ester 4 had improved in vivo κ-selectivities compared to the unsubstituted parent compound (+)-S-2 and the para-substituted derivative 5. The improved κ-selectivities of 3 and 4 and the different agonist and antagonist potencies of 3 and 5 may be explained respectively by the existence of multiple κ agonist binding sites and distinct agonist and antagonist binding sites. In view of the antagonist selectivity and the apparent irreversible binding of DIPPA to κ receptors, it may serve as a useful pharmacologic or biochemical tool to investigate κ opioid receptors.

Original languageEnglish (US)
Pages (from-to)4490-4498
Number of pages9
JournalJournal of medicinal chemistry
Volume37
Issue number26
DOIs
StatePublished - Dec 1 1994

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