title: Targeting delta opioid receptors for pain treatment: drugs in phase I and II clinical development.
abstract: Opioids are widely used to treat severe pain. Most clinically used opioids activate µ-opioid receptors (MOR). Their ligands induce potent analgesia but also adverse effects. The δ-opioid receptor (DOR) is another member of the opioid receptor family that has been under intense investigation with the aim to avoid MOR-induced side effects. Areas covered: This article reviews DOR ligands which appeared to be promising after preclinical evaluation. A literature search using Pubmed, Cochrane library, ClinicalTrials.gov, EudraCT, AdisInsight database and EBSCO Online Library was conducted. Out of numerous newly synthesized molecules, only few candidates entered phase I and/or II clinical investigation. The publicly accessible results are presented here. Expert opinion: Many compounds showed potent DOR-specific pain inhibition in preclinical studies. ADL5859 and ADL5747 entered clinical trials and successfully passed phase I. However, in phase II studies the primary endpoint (pain reduction) was not met and further investigation was terminated. A third compound, NP2, is in phase II clinical evaluation and results are pending. These findings suggest a potential of DOR ligands according to preclinical studies. Further clinical research and secondary analysis of unpublished data is needed to identify molecules which are useful in humans.
authors.affiliation: a Klinik für Anästhesiologie und operative Intensivmedizin , Charité Campus Benjamin Franklin, Freie Universität Berlin , Berlin , Germany.
authors.forename: Viola
authors.initials: V
authors.lastname: Spahn
authors.affiliation: a Klinik für Anästhesiologie und operative Intensivmedizin , Charité Campus Benjamin Franklin, Freie Universität Berlin , Berlin , Germany.|b Multifunctional Biomaterials for Medicine , Helmholtz Virtual Institute , Teltow , Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Stein
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D015195:Drug Design; D006801:Humans; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D017465:Receptors, Opioid, delta / Q000819:agonists*; D013141:Spiro Compounds / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000701:Analgesics, Opioid; D001549:Benzamides; D001578:Benzopyrans; C544196:N,N-diethyl-3-hydroxy-4-(spiro(chromene-2,4'-piperidine)-4-yl)benzamide; C532570:N,N-diethyl-4-(5-hydroxyspiro(chromene-2,4'-piperidine)-4-yl)benzamide; D017465:Receptors, Opioid, delta; D013141:Spiro Compounds
keywords: Analgesia; delta opioid receptor; opioids; pain