Affinity profiles of novel delta-receptor selective benzofuran derivatives of non-peptide opioids.
Highly selective heterocyclic opioid ligands with potent delta-antagonist activity have been developed on the basis of the "message-address" concept. Using this strategy, benzofuran derivatives corresponding to the non-selective opioid antagonist, naloxone, and to the mu-opioid receptor selective agonists, oxymorphone and oxycodone, were synthesized. In vitro opioid receptor binding profiles and agonist/antagonist character of these compounds were determined in rat brain membrane preparations with highly selective radioligands. All three benzofuran derivatives displayed high affinities for the delta-opioid receptor, much less potency toward the mu-binding site, and were the least effective at the kappa-site. The results indicated that the addition of the bezofuran moiety to these fused ring opioids confers delta-receptor selectivity. The Na+ indices suggested a partial agonist character for oxymorphone- and oxycodone-benzofuran, and an antagonist character for naloxone-benzofuran. These compounds were capable of irreversible inhibition of opioid binding sites in a dose-dependent.
Institute of Biochemistry Biological Research Center, Hungarian Academy of Sciences, Szeged.
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D000818:Animals; D044482:Benzeneacetamides; D001572:Benzofurans / Q000494:pharmacology*; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism; D009270:Naloxone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D010098:Oxycodone / Q000031:analogs & derivatives / Q000494:pharmacology; D010111:Oxymorphone / Q000031:analogs & derivatives / Q000494:pharmacology; D011759:Pyrrolidines / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism; D014316:Tritium
D044482:Benzeneacetamides; D001572:Benzofurans; D004745:Enkephalins; D009842:Oligopeptides; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C060209:deltorphin II, Ala(2)-; D009270:Naloxone; D009271:Naltrexone; D020881:Enkephalin, D-Penicillamine (2,5)-; D010111:Oxymorphone; D010098:Oxycodone; C055382:naltrindole; C045444:U 69593