Opioid activity profiles indicate similarities between the nociceptin/orphanin FQ and opioid receptors.
Nociceptin (orphanin FQ) is the recently discovered peptide agonist for the orphan receptor opioid receptor-like 1 (ORL1). Despite the high sequence homology between ORL1 and the opioid receptors, most opioids lack affinity for the nociceptin receptor. The affinity and functional profile of opioids possessing activity at the nociceptin receptor was determined using [3H]nociceptin and nociceptin-stimulated [35S]GTPgammaS binding. The mu-opioid receptor-selective agonist lofentanil potently and competitively displaced [3H]nociceptin at rat brain receptors (IC(50) 62 nM). Lofentanil exhibited full agonism for enhancement of [35S]GTPgammaS binding to human recombinant ORL1 receptors (EC(50) 50 nM). The related piperidines ohmefentanyl and sufentanil and the nonselective opioid receptor agonist etorphine were less potent nociceptin receptor agonists. The kappa(1)+kappa(3)-opioid receptor agonist/mu-opioid receptor antagonist naloxone benzoylhydrazone was a pure antagonist at both rat brain and human ORL1 receptors. The nonselective opioid receptor partial agonist buprenorphine and the nonselective opioid receptor antagonist (-)-quadazocine exhibited pure antagonism at rat brain receptors, but displayed partial agonism at human ORL1 receptors. Thus, opioids displaying full agonism at the nociceptin receptor are also opioid receptor agonists, whereas opioids that are antagonists or partial agonists at the nociceptin receptor show antagonism or partial agonism at opioid receptors. In addition, the stereospecificity required at opioid receptors appears to be retained at the nociceptin receptor, since (+)-quadazocine is inactive at both receptors. These findings illustrate the structural and functional homology of the opioid recognition site on these two receptor classes and suggest that opioids may provide leads for the design of nonpeptide nociceptin receptor agonists and antagonists lacking affinity for the classical opioid receptors.
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sufentanil etorphine naloxone benzoylhydrazone Nociceptin ORL1 opioid receptor opioid receptor ORL1 orphanin FQ human ORL1 buprenorphine nociceptin receptor opioid receptor nociceptin receptor opioid receptors opioid receptors nociceptin receptor ORL1 opioid receptors nociceptin receptor opioid receptors (-)-quadazocine nociceptin receptor nociceptin receptor mu-opioid receptor ORL1 orphan receptor opioid receptor nociceptin receptor mu-opioid receptor opioid receptor-like 1 nociceptin (+)-quadazocine orphanin FQ opioid receptors [35S]GTPgammaS lofentanil Lofentanil [35S]GTPgammaS piperidines ohmefentanyl