CR4056 / Rottapharm Biotech - LARVOL DELTA

Imidazoline receptor targeting as a novel method of seizure control during nerve agent induced status epilepticus in a rat model. (Neuroscience 2024) - "Second line antiseizure drugs like levetiracetam, fosphenytoin, and valproate are only effective in approximately half of cases, which underscores a need to develop novel treatments that terminate SE when other options fail...Twenty minutes after onset of SE, rats received midazolam and a test treatment (CR4056, 2-BFI, agmatine) or control (saline)...Post-treatment mortality rates for CR4056 and 2-BFI were 2/13 and 3/12 respectively. Future work will include targeted blocking and reversal experiments to determine if imidazoline receptor antagonists can prevent or reverse the ability of dexmedetomidine to control SE."

Late-breaking abstract • Preclinical • CNS Disorders • Epilepsy • Vascular Neurology

Editorial: Women in science: pharmacological treatment of pain. (PubMed, Front Pain Res (Lausanne)) - No abstract available

Journal • CNS Disorders • Depression • Pain • Psychiatry

Sex differences in the antidepressant-like response and molecular events induced by the imidazoline-2 receptor agonist CR4056 in rats. (PubMed, Pharmacol Biochem Behav) - "Interestingly, these effects were exclusively observed in female rats, and independently of early-life conditions, suggesting some distinctive molecular underpinnings participating in the therapeutic response of CR4056 for both sexes. In conjunction, these results present CR4056 with an antidepressant-like potential, especially in female rats exposed to stress early in life, together with some neuronal correlates described in the context of these behavioral changes in females."

Journal • Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Pain • Psychiatry • FADD

Modulation of NMDA receptor activity by CR4056, an imidazoline-2 receptor ligand with analgesic properties. (PubMed, Front Pain Res (Lausanne)) - "Taken together, our results broad the understanding of the molecular mechanisms of CR4056 analgesic activity, involving the modulation of NMDAR activity. Therefore, we propose that the analgesic action of CR4056 and the neuroprotective effects in AD models may be mediated also by NMDAR inhibition."

Journal • Addiction (Opioid and Alcohol) • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Infectious Disease • Pain • Respiratory Diseases • GRIN2A

I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice. (PubMed, Int J Mol Sci) - "In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Immunology • Inflammation • Pain • APOE

Imidazoline Receptor System: The Past, the Present, and the Future. (PubMed, Pharmacol Rev) - "Existing data suggest that I receptors may represent a binding site at the Kir6.2-subtype ATP-sensitive potassium channels in pancreatic β-cells and may be involved in insulin secretion. Despite the elusive nature of their molecular identities, recent progress on drug discovery targeting imidazoline receptors (I and I) demonstrates the exciting potential of these compounds to elicit neuroprotection and to treat various disorders such as hypertension, metabolic syndrome, and chronic pain."

Journal • Review • Hypertension • Metabolic Disorders • Pain

A Randomized, Placebo-Controlled, Double-Blind, Phase II Clinical Trial of the First-in-Class Imidazoline-2 Receptor Ligand CR4056 in Pain from Knee Osteoarthritis and Disease Phenotypes (ACR-ARHP 2017) - "CR4056 is the first I2R ligand to show analgesic activity in humans. The compound was safe and effective in reducing knee OA pain in this very short phase II trial, especially in overweight and obese patients. This observation prompts longer-term trials and the exploration of possible links between the I2 pathway and the overweight or metabolic OA phenotype altered pain perception."

P2 data • Serious adverse event • Immunology • Inflammation • Osteoarthritis

Improved efficacy, tolerance, safety and abuse liability profile of the combination CR4056-morphine over morphine alone in rodent models. (PubMed, Br J Pharmacol) - "Our study points towards a selective synergism CR4056-morphine in analgesia, with the potential for their combination to have an improved safety and abuse liability profile over morphine alone. These findings support CR4056 development as opioid-sparing drug in multimodal analgesia."

Journal

Effects of imidazoline I2 receptor agonists on reserpine-induced hyperalgesia and depressive-like behavior in rats. (PubMed, Behav Pharmacol) - "2-BFI (3.2-10 mg/kg, intraperitoneally), phenyzoline (17.8-56 mg/kg, intraperitoneally), and CR4056 (3.2-10 mg/kg, intraperitoneally) all dose-dependently produced significant antinociceptive effects, which were attenuated by the I2R antagonist idazoxan. Only CR4056 significantly reduced the immobility time in the forced swim test in both vehicle-treated and reserpine-treated rats. These data suggest that I2R agonists may be useful to treat fibromyalgia-related pain and comorbid depression."

Journal • Preclinical

Efficacy and safety of the first-in-class imidazoline-2 receptor ligand CR4056 in pain from knee osteoarthritis and disease phenotypes: a randomized, double-blind, placebo-controlled phase 2 trial. (PubMed, Osteoarthritis Cartilage) - P2; "Although the primary endpoint was met in males only, this exploratory phase 2 trial shows that CR4056 might be an effective analgesic against knee OA pain, especially in overweight patients representing the metabolic OA phenotype. These findings, along with the broad-spectrum analgesic activity of CR4056 in animal models, warrant further clinical investigation in OA and other pain conditions."

Clinical • Journal • P2 data

CR4056, a powerful analgesic imidazoline-2 receptor ligand, inhibits the inflammation-induced PKCε phosphorylation and membrane translocation in sensory neurons. (PubMed, Br J Pharmacol) - "Our results demonstrate that CR4056 shares the ability to inhibit PKCε translocation with other analgesics. Whether the inhibition of PKCε involves binding to specific subtype(s) of I2 receptors should be further investigated. If so, this would be a new mode of action of a highly specific I2 receptor ligand."

Journal

Mechanisms of imidazoline Ireceptor agonist-induced antinociception in rats: involvement of monoaminergic neurotransmission. (PubMed, Br J Pharmacol) - "IR agonist-induced antinociception is mediated by serotonergic and noradrenergic mechanisms with 5-HT, 5-HT, and α-adrenergic receptors being particularly important. In contrast, the hypothermic and discriminative stimulus effects of IR agonists are mediated by distinct, independent mechanisms."

Journal • Preclinical