Dopergin (lisuride) / Bayer - LARVOL DELTA

A comparative study of effects of DOM and lisuride on neuronal activity in nucleus accumbens of freely moving rats. (PubMed, Eur J Pharmacol) - "These differences in electrophysiological responses might contribute to the distinct behavioral effects associated with hallucinogenic and non-hallucinogenic properties of these compounds. The results will provide electrophysiological evidence for treatment of related psychotomimetic symptoms."

Journal • Preclinical

Neurochemical characterization of 5-HT2AR partial agonists with simultaneous PET-MRI. (PubMed, J Cereb Blood Flow Metab) - "We performed simultaneous positron emission tomography (PET) and pharmacological magnetic resonance imaging (phMRI) in anesthetized nonhuman primates (NHP; N = 3) to examine partial agonists with varying 5-HT2AR affinities and selectivity profiles: psilocybin (30, 60, and 90 µg/kg), lisuride (5 µg/kg), and 25CN-NBOH (15 µg/kg)...We speculate that the temporal and spatial differences in hemodynamic responses of the three agonists could stem from mixed affinity profiles. This work provides an understanding of pharmacological impacts of mixed serotonergic agonists being pursued as therapeutics for psychiatric conditions, offering valuable insights for future drug applications and development strategies."

Journal • Anesthesia • Psychiatry

Snapshot of 5-HT 2A receptor activation in the mouse brain via IP 1 detection. (PubMed, bioRxiv) - "We observed that IP 1 levels in frontal cortex homogenates from mice treated with LSD and lisuride vary in magnitude, consistent with LSD's 5-HT 2A R agonism and psychedelic nature, and lisuride's lack thereof. MDMA evoked an increase of IP 1 signal in the frontal cortex that were not matched by the serotonin precursor 5-HTP or the serotonin reuptake inhibitor fluoxetine. We attribute differences in the readout primarily to the indirect stimulation of 5-HT 2A R by MDMA via serotonin release from its presynaptic terminals. This methodology enables capturing a snapshot of IP 1 turnover in the mouse brain that can provide mechanistic insights in the study of psychedelics and other serotonergic agents pharmacodynamics."

Journal • Preclinical

Characterizing non-psychedelic psychedelics: phenotypic fingerprinting of lisuride and LSD (Neuroscience 2024) - "Combined, these results suggest that although lisuride may not be acting as a traditional psychedelic, it does impact both motor and cognitive function. Further, robust preclinical phenotypic characterization beyond the HTR is important for identifying non-hallucinogenic compounds to move forward for clinical development."

CNS Disorders • Depression • Mental Retardation • Psychiatry

Psilocybin vs. lisuride: similarities and differences in their serotonergic, dopaminergic, sedative-, anxiogenic-, and antidepressant-like effects (Neuroscience 2024) - "Both drugs decrease 5-HT cell firing but only psilocybin’s effect was 5-HT2A mediated, only psilocybin produced an anxiolytic-like effect, and only lisuride yielded an antidepressant-like effect. Further research is ongoing to better understand the intrinsic activity of these compounds on 5-HT and DA sub-receptors in different areas."

CNS Disorders

Reversal of propofol or isoflurane anesthesia, with concurrent restoration of functional connectivity, by intravenous administration of the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (Neuroscience 2024) - "Additionally, intravenous delivery of a non-psychedelic 5-HT2A agonist (lisuride, 0.05 mg/kg) neither reversed propofol anesthesia nor induced any significant changes in gamma functional connectivity. To our knowledge, this is the first report of psychedelic-mediated, 5-HT2A receptor-dependent reversal of general anesthesia and restoration of functional connectivity. These data encourage translational study of serotonergic psychedelics, particularly DOI, as reversal agents for unconsciousness."

CNS Disorders

DReAmocracy: A Method to Capitalise on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing. (PubMed, Int J Mol Sci) - "Top-scored drugs for Alzheimer's Disease include agomelatine, mirtazapine and vortioxetine; for Parkinson's Disease, they include apomorphine, pramipexole and lisuride; for Huntington's, they include chlorpromazine, fluphenazine and perphenazine; and for Multiple Sclerosis, they include zonisamide, disopyramide and priralfimide. Overall, DReAmocracy is a methodology that focuses on leveraging the existing drug-related experimental and/or computational knowledge rather than a predictive model for drug repurposing, offering a quantified aggregation of existing drug discovery results to (1) reveal trends in selected tracks of drug discovery research with increased resolution that includes modes of action, targeted pathways and initial indications for the investigated drugs and (2) score new candidate drugs for repurposing against a selected disease."

Journal • Alzheimer's Disease • CNS Disorders • Huntington's Disease • Movement Disorders • Multiple Sclerosis • Parkinson's Disease

Testing of putative antiseizure medications in a preclinical Dravet syndrome zebrafish model. (PubMed, Brain Commun) - "Thus far, we have screened more than 3000 drug candidates in scn1lab zebrafish mutants, identifying valproate, stiripentol, and fenfluramine e.g. Food and Drug Administration-approved drugs, with clinical application in the Dravet syndrome population...Here, we curated a list of nine anti-seizure drug candidates recently identified by other groups using preclinical Dravet syndrome models: 1-Ethyl-2-benzimidazolinone, AA43279, chlorzoxazone, donepezil, lisuride, mifepristone, pargyline, soticlestat and vorinostat...Surprisingly, soticlestat induced frank electrographic seizure-like discharges in wild-type control zebrafish. Taken together, our results failed to replicate clear anti-seizure efficacy for these drug candidates highlighting a necessity for strict scientific standards in preclinical identification of anti-seizure medications."

Journal • Preclinical • CNS Disorders • Epilepsy

Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited. (PubMed, ACS Pharmacol Transl Sci) - "Overall, our findings show that lisuride is an ultrapotent 5-HT1A agonist in C57BL/6J mice, limiting its use as a 5-HT2A ligand in mouse studies examining acute drug effects. Results also indicate that the 5-HT2A partial agonist-antagonist activity of lisuride explains its lack of psychedelic effects."

Journal • ARRB1

Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT receptor the unique player? (PubMed, Neuropsychopharmacology) - "Here, we addressed these issues by investigating the effect of two psychedelics of different chemical families, DOI and psilocybin, and a non-hallucinogenic 5-HTR agonist, lisuride, in a chronic despair mouse model exhibiting a robust depressive-like phenotype...Moreover, neither 5-HTR blockade nor dopamine D or D receptor blockade affected the antidepressant-like effects of psilocybin in 5-HT mice. Collectively, these findings indicate that 5-HTR agonists can produce antidepressant-like effects independently of hallucinogenic properties through mechanisms involving or not involving the receptor."

Journal • Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

Identification of 5-HT receptor signaling pathways associated with psychedelic potential. (PubMed, Nat Commun) - "We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT partial agonists (e.g., lisuride) are non-psychedelic...We also demonstrate that β-arrestin-biased 5-HT receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics."

Journal • ARRB1

Identification of the 5-HT2A Signaling Pathways Responsible for Psychedelic Potential (ACNP 2023) - "These results indicate that 5-HT2A-Gq activation but not βArr2 recruitment serves a key role in mediating psychedelic-like behavioral effects. In addition, it appears that a threshold level of Gq efficacy is required to induce the HTR in mice and psychedelic effects in humans, potentially explaining why certain 5-HT2AR agonists such as lisuride are non-psychedelic. These results have implications for drug development because it may be possible to identify 5-HT2A-Gq partial agonists that do not induce the HTR and lack strong psychedelic effects in humans but retain sufficient efficacy to induce therapeutic neurophysiological effects such as neuroplasticity via 5-HT2AR."

CNS Disorders • Depression • Psychiatry • ARRB1

Prophylactic effects of arketamine, but not hallucinogenic psychedelic DOI nor non-hallucinogenic psychedelic analog lisuride, in lipopolysaccharide-treated mice and mice exposed to chronic restrain stress. (PubMed, Pharmacol Biochem Behav) - "Anesthetic ketamine and classical psychedelics that act as 5-hydroxytryptamine-2A receptor (5-HTR) agonists demonstrated rapid and sustained antidepressant actions in patients with treatment-resistant depression. Pretreatment with aketamine, but not DOI and lisuride, significantly ameliorated the increased FST immobility time, the reduced sucrose preference in the sucrose preference test, and the decreased expression of PSD-95 in the PFC of CRS-exposed mice. These findings suggest that, unlike to arketamine, both DOI and lisuride did not exhibit long-lasting prophylactic effects in mouse models of depression."

Journal • Preclinical • Anesthesia • CNS Disorders • Depression • Inflammation • Psychiatry

Determining the role of dose and 5-HT2AR activation in the lasting affective behavioral effects of psilocybin (Neuroscience 2023) - "Moreover, 5-HT2AR activation, while necessary appears to not be sufficient for the emergence of psilocybin effects, as shown by the absence of lisuride effects. These results highlight 5-HT2AR as the key player in psilocybin-induced behavioral effects, with future work focusing on their molecular and functional correlates."

CNS Disorders • Mental Retardation • Psychiatry

Transient elevation of corticosterone supports psilocybin's anxiolytic effects (Neuroscience 2023) - "This dose-dependent interaction correlates with psilocybin-induced increases in CORT levels that peak at 15 min and return to baseline by 4 h. In addition, the non-hallucinogenic compound lisuride and NDMAR antagonist ketamine were used and demonstrated a transient increase in corticosterone concentrations at 15 min and returned to baseline by 4 h. When tested in the novelty suppressed feeding test, all three compounds reduced the latency to feed 4 h post-injection. Cleared whole-brains were imaged, cell-counted, registration to the Alan Brain Atlas as preliminary data. These results suggest that psilocybin-induced stress response, and increased plasma CORT levels, are supportive of the observed anxiolytic effects."

CNS Disorders • Mental Retardation • Psychiatry

The G protein biased serotonin 5-HT2A receptor agonist lisuride exerts anti-depressant drug-like activities in mice. (PubMed, Front Mol Biosci) - "Clozapine, SCH23390, and GR127935 restored PPI in both βArr1 genotypes. Using vesicular monoamine transporter 2 mice, lisuride reduced immobility times in tail suspension and promoted a preference for sucrose that lasted up to 2 days. Together, it appears βArr1 and βArr2 play minor roles in lisuride's actions on many behaviors, while this drug exerts anti-depressant drug-like responses without hallucinogenic-like activities."

Journal • Preclinical • Nicotine Addiction

Effects of Tiliroside and Lisuride Co-Treatment on the PI3K/Akt Signal Pathway: Modulating Neuroinflammation and Apoptosis in Parkinson's Disease. (PubMed, Biomedicines) - "Antioxidant markers such as superoxide dismutase (SOD), catalase, and reduced glutathione significantly improved compared to the MPTP-induced control group. This study shows that using Til and Lis together effectively treats MPTP-induced PD in rats, yielding results comparable to an 8 mg/kg dose of levodopa, highlighting their potential as promising Parkinson's treatments."

IO biomarker • Journal • CNS Disorders • Inflammation • Lymphoma • Movement Disorders • Oncology • Parkinson's Disease • BCL2 • CASP3 • CAT • TNFA

Cerebral serotonin 2a receptor occupancy of psychedelic and non-psychedelic compounds as measured in vivo in pigs (ECNP 2023) - "The drugs were injected IV as a bolus over approximately 30-60 sec, and [11C]Cimbi-36 was injected 30 sec after injection with psilocybin, 5 min after injection with lisuride, 25 min after injection with LSD and 5 min after injection with tabernanthalog (TBG) [2]...Conclusions We have here for the first time established in vivo the dose 5-HT2AR occupancy curves for a range of psychedelic versus non-psychedelic 5-HT2AR compounds. The data allows for comparison of behavioral outcomes in terms of head-twitch response across different 5-HT2AR agonists in future studies."

Preclinical • CNS Disorders

Transient Elevation of Plasma Glucocorticoids Supports Psilocybin-Induced Anxiolysis in Mice. (PubMed, ACS Pharmacol Transl Sci) - "Anxiolytic-like effects were also observed at 4 h following treatment with the nonpsychedelic 5-HT agonist lisuride at a dose causing a similar increase in plasma glucocorticoids as that seen with psilocybin, as well as following stress-induced (via repeated injection) glucocorticoid release alone...The long-term anxiolytic effects of psilocybin were lost when psilocybin was administered to animals with ongoing chronic elevations in plasma corticosterone concentrations. Overall, these experiments indicate that acute, resolvable psilocybin-induced glucocorticoid release drives the postacute anxiolytic-like effects of psilocybin in mice and that its long-term anxiolytic-like effects can be abolished in the presence of chronically elevated plasma glucocorticoid elevations."

Journal • Preclinical • Mood Disorders • Psychiatry

Designing lisuride intranasal nanocarrier system for reduction of oxidative damage with enhanced dopamine level in brain for Parkinsonism. (PubMed, J Psychiatr Res) - "When lisuride NE was administered intranasally resulted in considerably higher dopamine concentrations (17.48 ± 0.05 ng/mL) in comparison to rats receiving haloperidol (7.28 ± 0.02 ng/mL). From study, it is suggested that NE is a possible strategy to deliver lisuride intranasally to lower free radical damage and prevent the biochemical alterations associated with Parkinson's disease."

Journal • CNS Disorders • Movement Disorders • Otorhinolaryngology • Parkinson's Disease

A Novel Methodology for Benchmarking 5 - HT2A Receptor Engagement in the Mouse Brain (CINP 2023) - " We demonstrate that the IP1 production in the mouse frontal cortex of two structurally similar drugs, LSD and lisuride, varies in magnitude, further suggesting that low efficacy agonists like lisuride might operate as phenotypical 5-HT2A antagonists as observed in vivo...We also observed that MDMA evoked an increase in IP1 signals in the frontal cortex that were not matched by the serotonin precursor 5- HTP or the serotonin uptake inhibitor fluoxetine. In the hopes of shedding light on the drug interaction with 5-HT2A, we developed a novel methodology to determine 5-HT2A engagement of the canonical Gq pathway in the mouse brain. This readout is a composite of pharmacokinetic and pharmacodynamic dynamics that reflect drug ADME as well as target engagement interactions, thus serving as a valuable benchmarking platform for psychedelic-like drug development and for investigating the relationship between the molecular events that unfold from drug-receptor interactions in..."

Preclinical

Rearing behaviour in the mouse behavioural pattern monitor distinguishes the effects of psychedelics from those of lisuride and TBG. (PubMed, Front Pharmacol) - "Finally, discriminant analysis was able to distinguish all four psychedelics from lisuride and TBG based on behavioural performance alone. Thus, increased rearing in mice could provide additional evidence of behavioural differences between hallucinogenic and nonhallucinogenic 5-HT agonists."

Journal • Preclinical

Structure-based design of serotonin 2A receptor agonists as a novel treatment for depression (ACS-Sp 2023) - "Current known agonists of this receptor include various non-hallucinogenic molecules, such as serotonin and lisuride, as well as hallucinogenic molecules such as lysergic acid diethylamide (LSD) and psilocybin...Ligands designed will then be simulated through molecular dynamics.Although results are currently in the preliminary stages, we are encouraged by the ability of the computational chemistry methods to accurately model the serotonin 2a receptor within a membrane in silico. The results from this study will ideally shed light on the effect certain agonists have on the serotonin receptor that can be used in the design of future antidepressants."

CNS Disorders • Depression • Fatigue • Mood Disorders • Psychiatry • Suicidal Ideation

Rapid antidepressant-like effect of non-hallucinogenic psychedelic analog lisuride, but not hallucinogenic psychedelic DOI, in lipopolysaccharide-treated mice. (PubMed, Pharmacol Biochem Behav) - "In this study, we compared the effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HTR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HTR and 5-HTR agonisms), and the novel antidepressant (R)-ketamine on depression-like behavior and the decreased dendritic spine density in the brain of lipopolysaccharide (LPS)-treated mice. This study suggests that antidepressant-like effect of lisuride in LPS-treated mice is not associated with 5-HTR-related psychedelic effects. It is, therefore, unlikely that 5-HTR may play a major role in rapid-acting antidepressant actions of psychedelics although further detailed study is needed."

Journal • Preclinical • CNS Disorders • Depression • Psychiatry

Rigorous evaluation of putative antiseizure drugs in scn1lab mutant zebrafish (Neuroscience 2022) - "Among these, scn1lab mutant zebrafish that exhibit spontaneous seizure-like activity were developed in our laboratory and successfully identified “standard-of-care” ASMs used in this patient population (e.g., valproate, benzodiazepines, stiripentol), as well as novel serotonin-modulating drugs (e.g., fenfluoramine, clemizole, and lorcaserin)...Here, we curated a list of 9 antiseizure drug candidates identified in the preclinical DS model literature: donepezil, soticlestat, lisuride, vorinostat, mifepristone, pargyline, 1-EBIO, chlorzoxazone and AA43279...Interestingly, we found exposing WT larvae to soticlestat induced seizure-like discharges. As our results failed to replicate clear antiseizure efficacy for any of the drugs tested, and yielded a potential adverse side-effect for at least one, it highlights the necessity for strict scientific standards in preclinical identification of effective patient treatment options."

CNS Disorders • Epilepsy