PF-04856880

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 Further clinical research and secondary analysis of unpublished data is needed to identify molecules which are useful in humans.

Kappa opioid (KOP) receptor antagonists and delta opioid (DOP) receptor agonists have antidepressant-like effects in animal tests and may be useful for treatment-resistant depression in humans. In this study, we examined whether the combination of a KOP receptor antagonist and a DOP receptor agonist would produce a better than additive effect (i.e. synergy). LY2444296 is a short-acting selective nonpeptide KOP receptor antagonist. ADL5859 is a selective nonpeptide DOP receptor agonist which does not produce seizures and EEG disturbances. Each compound and combinations of the two were examined in the forced swim test (FST) one h post injection, a screening test for antidepressant-like effect, in male adult C57BL/6J mice (Jackson Lab). LY2444296 [subcutaneous (s.c.) injection] at 10 and 30mg/kg, but not 3mg/kg, significantly decreased immobility time in a dose-dependent manner. Intraperitoneal (i.p.) injections of ADL5859 also reduced immobility time dose-dependently at doses of 3 and 10mg/kg, but not at 1mg/kg. An analysis was conducted using the method of Tallarida and Raffa (2010), which employed dose equivalence. The relative potency of the drugs was determined to be LY2444296: ADL5859=1:0.28, which was the dose ratio for combination studies. Six combinations of the two compounds were tested in mice at a fixed dose ratio. We found that LY2444296 and ADL5859 yielded significant synergistic effects for the antidepressant-like effect at the combined dose ranging from 3.84mg/kg to 9.0mg/kg. ADL5859 (10mg/kg), LY2444296 (30mg/kg) and their combined dose (3.84mg/kg) had no effects on locomotor activities. Since the two drugs have distinct pharmacological profiles, such a synergism will allow use of lower doses of both drugs to achieve desired antidepressant effects with fewer side effects.