Glasgow Meeting - May 2003

New Opioids on the Horizon – Structural Aspects and Clinical Applications.

Opioid agonists mimic the activity of the endogenous opioid peptides, the enkephalins, endorphins and dynorphins. These pentapeptides vary in their affinity for the opioid receptors, but none binds exclusively to one type. A new class of highly selective µ-selective endogenous peptides, the endomorphines endomorphin-1 and endomorphin-2, are thought to be the endogenous ligands for the µ-receptor (1).

Although the endogenous opioid peptides are analgesic, their clinical usefulness is severely limited by rapid biodegradation by peptidases. Enkephalinase inhibitors are analgesic in animals, and mixed inhibitors of enkephalin degrading enzymes are now undergoing preclinical trials (2). In animals intrathecal endomorphins have a strong analgesic action, suggesting a possible use of analogues of these compounds in the therapy of pain (3). There are also potent synergistic antinociceptive interactions between endomorphin-1 and both a2-agonists and the NMDA antagonist, S(+)-ketamine, and this interaction could be expolited therapeutically (4).

Currently available opioids have a number of side effects that limit their clinical usefulness; respiratory depression, inhibition of the GI motility, emesis, urinary retention, tolerance and dependence. While activation of cerebral µ1- and spinal µ2- receptors mediates the analgesia produced by most opioids, respiratory depression and reduced GI motility is thought to be caused by activation of µ2-receptors. Unfortunately, despite extensive searching, the pharmacological industry has failed to develop selective µ1-receptor agonists that would produce analgesia without the side effects of current drugs. The GI consequences of opioids can be moderated by the oral administration of opioid antagonists. Unfortunately, sufficient antagonist is usually absorbed to counteract the analgesic effects of the agonist. Selective postoperative inhibition of GI opioid receptors by an investigational antagonist (ADL 8-2698), with limited oral absorption, and which does not cross the blood-brain barrier, speeded recovery of bowel function and shortened the duration of hospitalisation after abdominal surgery (5,6). 

Many of the µ-opioid agonists have similar structural features, with a phenyl ring, tertiary nitrogen atom and a two-carbon fragment, which appear to play an important role in receptor activation and pharmacological activity. One approach to finding improved opioids with less side effects has been to modify this structure. A good example is remifentanil, where the addition of an ester moiety resulted in a compound with rapid esterase metabolism. Other structural modifications have not been so successful. Another approach is too look at drugs acting at other opioid receptors. κ-opioid receptor agonists do not induce respiratory depression. Unfortunately, they produce a spectrum of side effects including locomotor impairment, sedation, CNS disturbances and diuresis. One strategy for eliminating these adverse effects is to restrict access to the CNS, as opioids also are effective at peripheral nerve endings, particularly during inflammatory conditions. Recently, novel peptides have been developed with high peripheral selectivity for the κ-receptor and a long duration of action (7).

The first human study of a new mixed δ/μ/κ opioid receptor agonist (DPI3290/ORG 41793) has recently been reported (8). In animals this compound demonstrated strong analgesic activity with limited respiratory depression. Another potent opioid, 14-methoxymetopon, induced no respiratory depression in dogs and caused less hypotension and bradycardia than sufentanil (9). This compound may be an agonist at µ and κ receptors. All its actions were reversed by naltrexone.

Delta-receptors are involved in antinociception, and selective d-agonists are effective analgesics in animals. Delta-receptor agonists have relatively mild effects on respiration, and thus there is considerable interest in the development of this class of compounds for human use. Indeed, several non-peptide d-receptor agonists have been developed and some of these compounds have been studied in volunteers. A major problem with most d-agonists is a tendency to produce dose-dependent convulsions.

Soon after the cloning of the classical opioid receptors, an entirely new class of opioid receptor, the ‘opioid receptor like 1’ (ORL1), was identified. The endogenous ligand for ORL1 is nociceptin or orphanin FQ. In animals nociceptin induces analgesia when administered intrathecally but causes hyperalgesia and reverses opioid-induced analgesia when given intracerebroventricularly. The broad spectrum of pharmacological effects of nociceptin suggests multiple therapeutic applications for ORL1 receptor agonists and antagonists. The development of non-peptide nociceptin antagonists will almost certainly result in new pharmacological tools for the management of pain, anxiety and other pathological states (10). Of particular interest is that drugs interacting with the ORL1-receptor appear to be free of abuse potential and may indeed have anti-addictive properties.

References.

1. Goldberg IE, Rossi GC, Letchworth SR, et al. Pharmacological characterization of endomorphin-1 and endomorphin-2 in mouse brain. J Pharmacol Exp Ther 1998 ; 286: 1007-13.

2. Senokuchi K, Nakai H, Nagao Y, Sakai Y, Katsube N, Kawamura M. New orally active enkephalinase inhibitors: their synthesis, biological activity, and analgesic properties. Bioorganic Med Chem 1998;6:441-63.

3. Przewlocka B, Mika J, Labuz D, et al. Spinal analgesic action of endomorphins in acute, inflammatory and neuropathic pain in rats. Eur J Pharmacol 1999 ; 367: 189-96.

4. Horvath G, Joo G, Dobos I, et al. The synergistic antinociceptive interactions of endomorphin-1 with dexmedetomidine and/or S(+)-ketamine in rats. Anesth Analg 2001; 93:1018-24.

5. Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med 2001; 345: 935-940.

8. Somma J, Iselin Chavis I, Greenberg B, Weatherwax KJ, Glass PSA. Pharmacokinetics of DPI3290 a new opioid. Anesthesiology 1999;91:A-456.

9. Freye E, Schmidhammer H, Latasch L. 14-methoxymetopon, a potent opioid, induces no respiratory depression, less sedation, and less bradycardia than sufentanil in the dog. Anesth Analg 2000; 90: 1359-64.

10. Darland T, Grandy DK. The orphanin/FQ system: an emerging target for the management of pain. Br J Anaesth 1998;81:29-37.