title: [Selective opioid agonists and inhibitors of enkephalin degradation enzymes: pharmacological and clinical values].
abstract: A recently developed series of highly selective and systemically active delta-agonists such as Tyr-X-Gly-Phe-Leu-Thr(OtBu), with X = D-Ser (OtBu) in BUBU and X = D-Cys(OtBu) in BUBUC, and complete inhibitors of enkephalin metabolism (Kelatorphan, RB 38A, RB 101) have enabled the major role played by mu-opioid receptors in supraspinal analgesia to be demonstrated. This is in agreement with the results of in vivo mu-receptor occupancy measured by taking into account the cross-reactivity of the delta-ligand for mu-sites. In contrast mu and delta binding sites seem to act independently to control pain at the spinal level. Strong analgesic effects can also be obtained by complete protection of tonically or phasically released endogenous enkephalins with mixed inhibitors. Chronic i.c.v. administration of the mu agonist DAMGO, led to a severe naloxone precipitated withdrawal syndrome whilst a weak dependence was seen with the delta agonist, DSTBULET or with RB 38A and none after repeated i.p. injection of RB 101, a systemically active mixed inhibitor. Moreover, chronic administration of RB 101 did not induce antinociceptive tolerance, a major side effect observed during chronic administration of opiates. These differences could be related to a more efficient and selective stimulation of opioid receptors by the endogenous enkephalins. This suggest that the large changes in receptor density, adenylate cyclase activity or phosphorylation of proteins following chronic morphine treatment is not significantly triggered by occupation of the opioid receptors by their natural ligands. All these data emphasize the interest in developing delta-agonists and mixed inhibitors with appropriate bioavailability for clinical evaluation.
authors.affiliation: Université René Descartes, Département de Chimie Organique, U266 INSERM, URA498 CNRS, Paris.
authors.forename: F
authors.initials: F
authors.lastname: Noble
authors.forename: B P
authors.initials: BP
authors.lastname: Roques
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D004723:Endorphins / Q000145:classification* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism*; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism
chemical_list: D004723:Endorphins; D011480:Protease Inhibitors; D011957:Receptors, Opioid; D000626:Aminopeptidases
vernacular_title: Agonistes opioïdes sélectifs et inhibiteurs des enzymes de dégradation des enképhalines: intérêts pharmacologiques et cliniques.