OSU6162 / NeuroSearch, Pfizer - LARVOL DELTA

Genetic liability for anxiety and treatment response to the monoamine stabilizer OSU6162 in alcohol dependence: a retrospective secondary analysis. (PubMed, Pharmacol Rep) - "These preliminary findings suggest that anxiety PRS may help predict response to OSU6162 treatment in AD. Further research with larger cohorts and more comprehensive genetic data is needed to confirm these results and advance personalized medicine approaches for alcohol use disorder."

Clinical • Journal • Retrospective data • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Interactions between dopaminergic and serotonergic receptors underlie the complex impact of the dopamine stabiliser (-) OSU6162 on psychomotor activity (ECNP 2024) - " In rats, interactions between (-)-OSU6162 and the dopamine releaser amphetamine were investigated by assessment of locomotor activity and extracellular dopamine levels in the dorsal striatum using in vivo microdialysis. These Results suggest the impact of (-)-OSU6162 on psychomotor activity to include the interaction of antagonism of D2 autoreceptors and positive allosteric modulation of postsynaptic D2 receptors, as well as partial agonism of the 5-HT2A receptor."

CNS Disorders • Mood Disorders • DRD2

OSU6162 in Bipolar Depression (OBID) (clinicaltrials.gov) - P2 | N=22 | Recruiting | Sponsor: Göteborg University | Trial completion date: Sep 2023 ➔ May 2027 | Trial primary completion date: May 2023 ➔ May 2026

Trial completion date • Trial primary completion date • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

Preclinical support for antidepressant and anxiolytic effects of the dopamine stabiliser (-)-OSU6162 (ECNP 2023) - "The substance exerts psychomotor activation in rodents habituated to their environment and psychomotor inhibition in amphetamine treated-, as well as treatment naïve but active and exploring rodents. The dopamine stabiliser (-)-OSU6162 showed behavioural effects in preclinical rat models of antidepressant and anxiolytic response. The effects are likely due to preferential blockade of the D2 auto receptor leading to enhanced dopamine release and hence enhanced activation of postsynaptic D2 receptors not antagonized by (-)-OSU6162. As (-)-OSU6162 is exceptionally well tolerated, the results justify clinical studies exploring the possible antidepressant and anxiety-reducing effects of the drug."

Preclinical • CNS Disorders • Depression • Mood Disorders • Psychiatry

ODEN: OSU6162 as add-on in SSRI/SNRI-resistant Depression (clinicaltrials.gov) - P2 | N=180 | Recruiting | Sponsor: Göteborg University | N=72 ➔ 180

Enrollment change • CNS Disorders • Depression • Mood Disorders • Psychiatry • BDNF • CRP • IL6 • TNFA

Combined treatment with Sigma1R and A2AR agonists fails to inhibit cocaine self-administration despite causing strong antagonistic accumbal A2AR-D2R complex interactions: the potential role of astrocytes. (PubMed, Front Mol Neurosci) - "Ex vivo studies using the A2AR agonist CGS21680 also suggested the existence of enhanced antagonistic accumbal A2AR-D2R allosteric interactions after treatment with OSU-6162 during cocaine self-administration. This can lead to increased activation of the A1R protomer in a putative A1R-A2AR-D2R complex that modulates glutamate release in the presynaptic glutamate synapse. We hypothesized that the integration of changes in presynaptic glutamate release and postjunctional heteroreceptor complex signaling, where D2R plays a key role, result in no changes in the firing of the GABA anti-reward neurons, resulting in no reduction in cocaine self-administration in the present experiments."

Journal

Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use. (PubMed, Mol Psychiatry) - "Finally, the use of the monoamine stabilizer OSU6162, previously reported to correct hypodopaminergic states, transiently decreased compulsive-like alcohol self-administration in vulnerable rats. These results suggest a potential critical role of tonic nigrostriatal hypodopaminergic states in alcohol addiction and provide new insights into our understanding of the neurobiological mechanisms underlying compulsive alcohol use."

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

Behavioral effects of the monoamine stabilizer (-)-OSU6162 in the forced swim and context conditioned fear tests (Neuroscience 2022) - "(-)-OSU6162 showed anxiolytic- and antidepressant-like efficacy in the context-conditioned freezing and forced swim tests. Atypical antipsychotics are prescribed as mono- or adjunctive therapy for difficult-to-treat depressive and anxiety disorders, but lack of tolerability is cause for discontinuation. The pharmacological similarity between these compounds and the better tolerated monoaminergic stabilizer (-)-OSU6162, in combination with the results described above, imply a therapeutic prospect for use of (-)-OSU6162 against mood disorders."

CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Synthesis of Stereoenriched Piperidines via Chemo-Enzymatic Dearomatization of Activated Pyridines. (PubMed, J Am Chem Soc) - "The key step involves a stereoselective one-pot amine oxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymatic approach has proved useful for key transformations in the syntheses of antipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib."

Journal • CNS Disorders • Oncology • Ovarian Cancer • Solid Tumor

Behavioural effects of the monoamine stabilizer (-)-OSU6162 in the forced swim and context conditioned fear tests (ECNP 2022) - "The pharmacological similarities between these compounds and (-)-OSU6162, in combination with the better clinical tolerance displayed by the monoaminergic stabiliser implies a therapeutic prospect for use against mood disorders. The Result s of this study are indicative of (-)-OSU6162 as a possible remedial approach for treatment-refractory anxiety and depressive disorders with a possible lack of the adverse effects commonly following administration of atypical antipsychotics."

CNS Disorders • Depression • General Anxiety Disorder • Major Depressive Disorder • Mood Disorders • Psychiatry

OSU6162 in Bipolar Depression (OBID) (clinicaltrials.gov) - P2 | N=22 | Recruiting | Sponsor: Göteborg University

New P2 trial • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

(-)-OSU6162 in the treatment of fatigue and other sequelae after aneurysmal subarachnoid hemorrhage: a double-blind, randomized, placebo-controlled study. (PubMed, J Neurosurg) - "Fatigue and other sequelae after aSAH were similarly alleviated by treatment with (-)-OSU6162 and placebo. (-)-OSU6162 improved fatigue, as measured with the FSS score, significantly in patients with complete RTW. There seemed to be synergetic effects of (-)-OSU6162 and medications interfering with dopaminergic pathways that should be explored further. The strong placebo response may be exploited in developing nonpharmacological treatment programs for post-aSAH fatigue."

Clinical • Journal • Cardiovascular • CNS Disorders • Depression • Fatigue • Hematological Disorders • Mood Disorders • Psychiatry • Subarachnoid Hemorrhage

The monoamine stabilizer OSU6162 has anxiolytic-like properties and reduces voluntary alcohol intake in a genetic rat model of depression. (PubMed, Sci Rep) - "While there was no significant difference in alcohol intake between FSL and FRL, OSU attenuated alcohol intake in both strains. Conclusively, in addition to the compound's previously identified ability to suppress alcohol-mediated behaviors, OSU may also possess anxiolytic properties, warranting further clinical evaluation in both AUD and anxiety disorder settings."

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

Open-label study with the monoamine stabilizer (-)-OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome. (PubMed, Brain Behav) - "(-)-OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health-related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo-controlled double-blind trials."

Clinical • Journal • CNS Disorders • Depression • Fatigue • Infectious Disease • Psychiatry

Effects of the monoamine stabilizer, (-)-OSU6162, on cocaine-induced locomotion and conditioned place preference in mice. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Here, we tested the hypothesis that the monoamine stabilizers, (-)-OSU6162 ((3S)-3-(3-methylsulfonylphenyl)-1-propylpiperidine) and aripiprazole (7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one), prevent cocaine-induced behaviors. (-)-OSU6162 exerts a minor effect in reducing cocaine-induced stimulatory activity and context-related memories, which are responsible for triggering drug seeking. Further studies are required to establish whether (-)-OSU6162 could be a candidate drug for the treatment of cocaine addiction."

Journal • CNS Disorders • Mental Retardation • Psychiatry

Study Evaluating Efficacy and Safety of OSU6162 in the Treatment of Residual Symptoms After Stroke (clinicaltrials.gov) - P2; N=101; Completed; Sponsor: A Carlsson Research AB; Active, not recruiting ➔ Completed

Clinical • Trial completion • Cardiovascular

Pharmaco-fMRI in Patients With Traumatic Brain Injury: A Randomized Controlled Trial With the Monoaminergic Stabilizer (-)-OSU6162. (PubMed, J Head Trauma Rehabil) - "(-)-OSU6162 treatment had influences on functional brain activity, although the normalized regional BOLD response was observed in regions that were not a priori hypothesized to be sensitive to this particular treatment, and was not accompanied by any effects on in-scanner test performance or on fatigue."

Clinical • Journal • Fatigue • Vascular Neurology

OSU6162DB003: Study Evaluating Efficacy and Safety of OSU6162 in the Treatment of Residual Symptoms After Stroke (clinicaltrials.gov) - P2; N=101; Active, not recruiting; Sponsor: A Carlsson Research AB; Trial completion date: Mar 2020 ➔ Sep 2020

Clinical • Trial completion date • Cardiovascular

Effects of the monoamine stabilizer (-)OSU6162 on cognitive function in alcohol dependence. (PubMed, Psychopharmacology (Berl)) - "OSU treatment did not cause short-term cognitive side effects, further supporting the potential of OSU as a clinically feasible pharmacological treatment in AD patients. OSU treatment might improve future planning, verbal divergent thinking, and emotional recognition latency, which in turn may have a beneficial impact on alcohol use outcomes. Future studies are needed to confirm these preliminary findings."

Journal • Addiction (Opioid and Alcohol)

Effect of the monoaminergic stabiliser (-)-OSU6162 on mental fatigue following stroke or traumatic brain injury. (PubMed, Acta Neuropsychiatr) - "The most obvious beneficial effects of (-)-OSU6162 was on the patients' activity level, illustrated by the improvement on the FAI scale. Moreover, a subgroup of patients showed substantial improvements on the Mental Fatigue Scale. Based on these observed therapeutic effects, in conjunction with the good tolerability of (-)-OSU6162, this compound may offer promise for treating at least part of the symptomatology in patients suffering from stroke- or TBI-induced mental fatigue."

Journal • Cardiovascular • CNS Disorders • Fatigue • Mood Disorders • Vascular Neurology

Effect of the dopamine stabilizer (-)-OSU6162 on potentiated incubation of opioid craving after electric barrier-induced voluntary abstinence. (PubMed, Neuropsychopharmacology) - "Results suggest that voluntary abstinence induced by negative consequences of drug seeking can paradoxically potentiate opioid craving and relapse. We propose the dopamine stabilizer (-)-OSU6162 may serve as an adjunct pharmacological treatment to prevent relapse in male opioid users."

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