PPL-138 / Phoenix PharmaLabs - LARVOL DELTA

Preclinical Evaluation of Dual NOP/Mu Partial Agonists for Methamphetamine Use Disorder. (PubMed, Pharmaceuticals (Basel)) - " PPL-138 and PPL-143 are structurally related bifunctional NOP/mu partial agonists that exhibit greater efficacy at NOP than at mu receptors, with PPL-143 showing the highest NOP efficacy. The findings support mixed mu/NOP partial agonists as a promising pharmacological strategy for treating MUD, while also indicating a potential for increased drug seeking under certain conditions. Notably, enhancing the NOP component does not appear to meaningfully improve either the safety profile or the anti-meth efficacy of these bifunctional ligands."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry

Testing the effect of the non-selective opioid PPL-138 in a model of alcohol relapse in the context of PTSD. (PubMed, Neuropharmacology) - "These results support the efficacy of pharmacological modulation of the opioid system in reducing both traumatic-like stress-induced escalation of alcohol-seeking behavior and cue-induced relapse associated with heightened anxiety, specifically in female rats. Classifying individuals based on traumatic stress-induced changes in alcohol-seeking behavior may provide a valuable model for evaluating pharmacological treatments for PTSD and AUD comorbidity."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Post-traumatic Stress Disorder • Psychiatry

The opioid partial agonist PPL-138 reduces alcohol self-administration in rats susceptible to post-traumatic stress disorder. (PubMed, Br J Pharmacol) - "Results support the efficacy of PPL-138 to attenuate behavioural traits attributable to PTSD and alcohol consumption associated with elevated anxiety in an AUD-PTSD population."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Mood Disorders • Pain • Post-traumatic Stress Disorder • Psychiatry

Buprenorphine Pharmacodynamics: A Bridge to Understanding Buprenorphine Clinical Benefits. (PubMed, Drugs) - "As a kappa opioid receptor (KOR) antagonist, buprenorphine reduces craving associated with addiction. Buprenorphine is a model opioid for the ordinal bifunctional analogs BU10038, BU08028 which have been shown to be potent analgesics in non-human primates without reinforcing effects and little to no respiratory depression."

Journal • PK/PD data • Review • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Pain • Psychiatry

Nociceptin Receptor-Related Agonists as Safe and Non-addictive Analgesics. (PubMed, Drugs) - "Moreover, mixed NOP/MOP receptor partial agonists (e.g., BU08028, BU10038, and AT-121) display potent analgesic effects when administered intrathecally or systemically, without eliciting adverse effects, such as respiratory depression, itch behavior, and signs of abuse liability. More importantly, cebranopadol, a mixed NOP/opioid receptor agonist with full efficacy at NOP and MOP receptors, produces robust analgesic efficacy with reduced adverse effects, conferring promising outcomes in clinical studies. A balanced coactivation of NOP and MOP receptors is a strategy that warrants further exploration and refinement for the development of novel analgesics with a safer and effective profile."

Journal • Review • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Pain • Psychiatry

OREX-1038: a potential new treatment for pain with low abuse liability and limited adverse effects. (PubMed, Behav Pharmacol) - "This study explored one of these ligands, OREX-1038 (BU10038), in several assays in rodents and nonhuman primates...This activity was coupled with limited effects on physiological signs (arterial pressure, heart rate, and body temperature) and no evidence of withdrawal after administration of naltrexone or discontinuation of treatment in monkeys receiving OREX-1038 daily. Over a range of doses, OREX-1038 was only transiently self-administered, which diminished rapidly to nonsignificant levels; overall, both OREX-1038 and buprenorphine maintained less responding than remifentanil. These results support the concept of dual mu and nociceptin/orphanin FQ peptide receptor partial agonists having improved pharmacological profiles compared with opioids currently used to treat pain."

Adverse events • Journal • CNS Disorders • Constipation • Depression • Gastroenterology • Gastrointestinal Disorder • Pain • Psychiatry

Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation. (PubMed, CNS Drugs) - "Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future."

Journal • Review • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Neuralgia • Oncology • Pain • Psychiatry • Substance Abuse

PPL-138 (BU10038): A bifunctional NOP/mu partial agonist that reduces cocaine self-administration in rats. (PubMed, Neuropharmacology) - "Blockade of NOP receptors with the selective antagonist J-113397 (5 mg/kg) did not prevent the PPL-138-induced suppression of cocaine self-administration, whereas blockade of mu-opioid receptors by naltrexone (1 mg/kg) reversed such effect. Consistently, treatment with morphine (1, 3, and 10 mg/kg) dose-dependently reduced IntA cocaine self-administration measures...However, suppression of cocaine self-administration was retained when subsequent PPL-138 treatments were administered 48 h apart. These findings demonstrate that the approach of combining partial NOP/mu-opioid activation successfully reduces cocaine use, but properties of PPL-138 seem to depend on the timing of drug administration."

Journal • Preclinical • Addiction (Opioid and Alcohol)

Therapeutic potentials of safe opioid analgesics targeting nociceptin/orphanin FQ peptide receptor (PubMed, Nihon Yakurigaku Zasshi) - "Bifunctional NOP/MOP receptor "partial" agonists, such as AT-121, BU08028, and BU10038, exert potent analgesic effects without MOP receptor-related side effects such as abuse liability, respiratory depression, physical dependence, and itching in NHPs. Furthermore, a mixed NOP/opioid receptor "full" agonist, cebranopadol, is undergoing several clinical trials, and the therapeutic advantage of the coactivation of NOP and MOP receptors has also been confirmed in humans. Therefore, this class of drugs that coactivate NOP and MOP receptors proposes a wide therapeutic range with fewer side effects, indicating a greater potential for the development of novel safer opioid analgesics."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Immunology • Pain • Psychiatry

Phoenix PharmaLabs Strengthens its Position as a Developer of Next Generation Pain Pharmaceuticals with the Acquisition of a Portfolio of NOP/Mu Agonist Compounds (Businesswire) - "Phoenix PharmaLab...today announced it has completed a license agreement with the University of Bath in England for exclusive rights to a portfolio of 25 NOP (Nociceptin) compounds...With both PPL-103 and the addition of PPL-138 to our portfolio, we believe we can help meet the unmet need for effective non-addicting treatment of moderate to severe pain."

Licensing / partnership • Pain