CommentariesOpioid analgesics as noncompetitive N-methyl-d-aspartate (NMDA) antagonists
Section snippets
Ketobemidone
Ketobemidone has been used in Europe for the last 50 years [32]. Based on clinical experience and clinical anecdotes, our group has tried to rationalize the clinical practice in order to select compounds suitable for the evaluation of a combination of opioid receptor agonism and noncompetitive NMDA receptor antagonism. The first compound tested was the potent opioid receptor agonist ketobemidone. Clinical anecdotes described patients with opioid-resistant pain that obtained almost complete
Methadone
Methadone, which is a synthetic μ opioid receptor agonist with an affinity for the μ receptor comparable to that of morphine [46], is used mainly for the treatment of drug addicts and, to a much lesser extent, as an analgesic. The reason for this is mainly that methadone has a highly variable biological bioavailability and a long and variable biological half-life, making it an optimal treatment for patients suffering from more complicated pain. When comparing the chemical structure of methadone
Dextropropoxyphene
Dextropropoxyphene is a weak opioid receptor agonist, which during the last 40 years has been used for the treatment of pain. The potency of dextropropoxyphene is much lower than that of morphine and codeine, reflecting a low affinity for the μ opioid receptor. Structurally, dextropropoxyphene is very similar to methadone (Fig. 1), suggesting that dextropropoxyphene may act as a non-competitive NMDA receptor agonist. In vitro studies subsequently have shown that dextropropoxyphene is a
Structure–activity relationships for morphine-like opioids
To further determine which structural characteristics are essential for the interaction of opioids with the NMDA receptor, we characterized a series of commercially available opioids with respect to their affinity for the [3H]MK-801-labelled NMDA receptor complex and in the rat cortical wedge preparation. As illustrated in Fig. 1, where the compounds are grouped according to the affinity determined in [3H]MK-801 binding, the presence of any polar group in or close to the 6 position of the ring
Conclusion
Although the finding that some opioids are weak non-competitive NMDA receptor antagonists in vitro has created much attention among clinicians, no clinical studies have evaluated the applicability of these compounds in the treatment of neuropathic pain conditions. The present knowledge about the action of these compounds with respect to NMDA receptors in vivo is so sparse that much basic research is still needed.
Acknowledgements
This work was supported by the Lundbeck Foundation. We wish to thank Dr. R. G. Hill, MSD Neuroscience Research Centre, Terlings Park, U.K., for very constructive suggestions.
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