idazoxan (RX 781094) / Houston Pharma - LARVOL DELTA

Studying the effects of I2-imidazoline receptor ligands in the 5xfad mouse model of Alzheimer's disease (ECNP 2025) - "In this study, we aimed to evaluate the effects of two selective I2-IR ligands, idazoxan and 2-(2-benzofuranyl)-2-imidazoline (2-BFI), in the 5xFAD transgenic mouse model of AD...Statistical significance was considered when p-values were < 0.05. Remarkably, significant changes were detected following treatment, highlighting the potential relevance of I2-IR modulation in cognitive processes."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Social stress worsens colitis through β-adrenergic-driven oxidative stress in intestinal mucosal compartments. (PubMed, bioRxiv) - "Mice were exposed to social disruption (SDR) stress and pre- treated with pharmacological antagonists targeting α2-adrenergic receptors (idazoxan), β-adrenergic receptor (β-AR) (propranolol), glucocorticoid receptor (mifepristone), or CRHR1 (antalarmin). These findings provide strong evidence that social stress sensitizes the gut to inflammation through β-adrenergic and NADPH oxidase-driven oxidative stress, highlighting potential therapeutic targets for mitigating stress-exacerbated IBD. Social disruption (SDR) and restraint stress (RST) activate distinct neuroendocrine pathways, with SDR driving epithelial ROS/RNS pathways via β-adrenergic signaling.β-adrenergic blockade prevents SDR-induced epithelial priming, microbial dysbiosis, and colitis exacerbation.NADPH oxidase inhibition with apocynin mitigates stress-induced oxidative stress and disease severity across different colitis models.Findings identify β-adrenergic and redox pathways as therapeutic targets for..."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • CCL2 • DUOX2 • NOS2

Mice mortality induced by dexmedetomidine is non-alpha2-adrenergic receptor-dependent. (PubMed, Toxicology) - "Furthermore, the immune modulator imiquimod, calcium sensitizer levosimendan, and TAAR1 antagonist RO5212773 decreased acute mortality without impacting chronic mortality induced by DMED. However, pretreatment with idazoxan or naloxone decreased the rise of serum creatine kinase and myoglobin. Collectively, these results highlighted the involvement of imidazoline receptors and opioid receptor in DMED mortality."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Anesthesia • Hematological Disorders • MB

Antagonism of the antinociceptive effects of fentanyl and the veterinary anesthetic xylazine in mice. (PubMed, J Pharmacol Exp Ther) - "In antagonism studies, naltrexone blocked fentanyl whereas yohimbine and the selective α2-adrenoreceptor antagonist, idazoxan, blocked the antinociceptive effects of xylazine...Haloperidol, a D2/σ1 antagonist, significantly shifted the potency of fentanyl and xylazine to the left...The experiments described here examine the pharmacology of these drugs alone and in combination using a model of antinociception in mice to better understand the underlying receptor mechanisms for fentanyl alone, xylazine alone, and fentanyl and xylazine in combination. The antinociceptive effects were predominantly a simple combination of opioid and α2-adrenoreceptor agonism."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Anesthesia

Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties. (PubMed, J Med Chem) - "The target engagement of 12d was demonstrated by suppression of the analgesic effect by pretreatment with idazoxan. Overall, 12d is a putative candidate for advancing preclinical phases and supports the modulation of I2-IRs as an innovative approach for therapeutics."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Immunology • Pain

Agmatine diminishes behavioral and endocrine alterations in a rat model of post-traumatic stress disorder. (PubMed, Neurosci Lett) - "Moreover, the effective dose of agmatine (40 µg/rat, icv) with imidazoline (I1 and I2) receptor antagonists Efaroxan (10 µg/rat, icv) and Idazoxan (4 µg/rat, icv) respectively does not show a significant effect on freezing. Agmatine and its combination with I1 and I2 agonists, normalized the altered freezing behavior due to SPS during CFR projecting its strong therapeutic implication for CFR in SPS induced-PTSD."

Journal • Preclinical • CNS Disorders • Post-traumatic Stress Disorder • Psychiatry

AN EXPLORATION OF POTENTIAL MECHANISM INVOLVED IN DEPRESSIVE-LIKE BEHAVIORS IN A RAT MODEL OF INFLAMMATORY BOWEL DISEASE: THE CRITICAL FUNCTION OF A2-ADRENOCEPTOR IN THE PRELIMBIC CORTEX (DDW 2024) - "The effective doses produced by dexmedetomidine and idazoxan in DSS model rats were higher than those in sham-operated rats. The present study provides evidence to further elucidate the involvement of PrL α -adrenoceptors in the regulation of depression particularly in IBD-related depression. Funding: Science and Technology Program of Xi 'an ( YXYJ0110)."

Preclinical • CNS Disorders • Depression • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Movement Disorders • Parkinson's Disease • Psychiatry • PRL

Estrogen-receptor status determines differential regulation of α1- and α2-adrenoceptor-mediated cell survival, angiogenesis, and intracellular signaling responses in breast cancer cell lines. (PubMed, Med Oncol) - "α1-AR inhibition reversed cellular proliferation and VEGF-A secretion by MCF-7 cells while α2-AR inhibition reversed the proliferation of MCF-7 and MDA MB-231 cells and VEGF-C secretion by MCF-7 cells. Taken together, breast cancer pathogenesis may be influenced by distinct α-AR-mediated signaling mechanisms on angiogenesis and lymphangiogenesis that are dependent on estrogen receptor status."

Journal • Preclinical • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • VEGFC

A Study of Idazoxan in Healthy Participants (clinicaltrials.gov) - P1 | N=150 | Recruiting | Sponsor: Terran Biosciences Australia Pty Ltd

Trial completion date • Trial primary completion date

A Study of Idazoxan in Healthy Participants (clinicaltrials.gov) - P1 | N=150 | Recruiting | Sponsor: Terran Biosciences Australia Pty Ltd | N=110 ➔ 150

Enrollment change

Sensitivity of arterial baroreflex as a prognostic marker in determining the properties of vegetotropic compounds (Neuroscience 2023) - "Sensitivity of ABR (SBR) was assessed by the Oxford method against the background of a single injection (i.v.) of the following vegetotropic drugs: non-selective β-blocker (β-B) propranolol (0.5 and 2 mg/kg), selective α2-B idazoxane (1 mg/kg) and developed in Armenia non-selective β-A with fobufol (0.5 and 2 mg/kg), α2-A beditin (3 and 15 mg/kg), ganglioplegic gangleron (3 mg/kg). SBR against the background of fobufol (0.5 mg/kg) was determined by extrapolation of the experimental data of the remaining 8 groups of animals. Using the same method, a model for predicting the membrane-stabilizing properties of β-B was developed.It is proposed to take into account differences in the impact effect of known antihypertensive drugs on hypertensive and chronotropic reactions in the Oxford ABR testing in predictive models when studying the properties of new vegetotropic drugs."

Biomarker • Reflex • CNS Disorders

Novel pharmacotherapy targeting the positive symptoms of schizophrenia (ECNP 2023) - "We identified several types of molecules, as CNS or non-CNS compounds acting with several mechanisms, which were investigated for treating PS of schizophrenia: - antidepressants: fluvoxamine; sertraline; duloxetine; trazodone; vortioxetine; reboxetine; mirtazapine; mianserine. - mood stabilizers: lamotrigine; pregabalin; valproate. - drugs acting on glutamatergic system or other neurotrasmitter: carbamazepine; glycine; D-cycloserine; D-serine; piracetam; memantine; diazepam; alprazolam; bitopertin; donepezil; idazoxan; lisdexamfetamine; methylphenidate; modafinil; selegiline. - non-CNS compounds primarily acting on the immune system: celecoxib; resveratrol; alpha-lipoic acid; N-acetyl cysteine; palmitoylethanolamide; methotrexate; minocycline; trimethoprim... In almost all studies these not-labeled treatments were tested as augmentation to antipsychotic therapy. However, better improvement of PS severity was only found for a limited number of CNS-compounds (lamotrigine,..."

CNS Disorders • Psychiatry • Schizophrenia • Suicidal Ideation

Noradrenergic projections regulate the acquisition of classically conditioned eyelid responses in wild-type and are impaired in kreisler mice. (PubMed, Sci Rep) - "Moreover, we demonstrate the involvement of adrenergic projection in eyelid classical conditioning, as clonidine prevents the appearance of eyelid conditioned responses in wild-type mice. In addition, hippocampal motor learning ability was restored in kreisler mice by administration of adrenergic antagonist drugs, and a synergistic effect was observed following simultaneous administration of idazoxan and naloxone."

Journal • Preclinical • Pain • ADORA2A

Novel pharmacotherapy targeting the positive symptoms of schizophrenia. (PubMed, Expert Opin Pharmacother) - "The most promising compounds include: lamotrigine, pro-cognitive-compounds (donepezil- in the short term, idazoxan and piracetam) and drugs acting partially or totally outside the Central Nervous System (CNS) (anti-inflammatory drugs: celecoxib, methotrexate; cardiovascular compounds: L-theanine, mononitrate isosorbide, propentofylline, sodium nitroprusside; metabolic regulators: diazoxide, allopurinol; others: bexarotene, raloxifene [in women]). Mirtazapine could be useful for treating negative symptoms without increasing the risk of a worsening of delusions/hallucinations. Nevertheless, the lack of replication of studies prevents to draw definitive conclusions and future studies are needed to confirm the findings presented in this overview."

Journal • Review • Cardiovascular • CNS Disorders • Psychiatry • Schizophrenia

6-Nitrodopamine potentiates contractions of rat isolated vas deferens induced by noradrenaline, adrenaline, dopamine and electric field stimulation. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "In tetrodotoxin (1 μM) pre-treated (30 min) RIEVD, pre-incubation with 6-ND (0.1 nM) did not cause leftward shifts in the concentration-dependent contractions induced by noradrenaline, adrenaline, or dopamine...However, when idazoxan (10 nM) and 6-ND (0.1 nM) were simultaneously pre-incubated (30 min), a significant potentiation of the EFS-induced contractions of the RIEVD was observed. 6-nitrodopamine causes remarkable potentiation of dopamine, noradrenaline, and adrenaline contractions on the RIEVD, due to activation of adrenergic terminals, possibly via pre-synaptic adrenoceptors."

Journal • Preclinical

A Study of Idazoxan in Healthy Participants (clinicaltrials.gov) - P1 | N=110 | Recruiting | Sponsor: Terran Biosciences Australia Pty Ltd | Not yet recruiting ➔ Recruiting

Enrollment open

A Study of the Safety, Tolerability and Pharmacokinetics of Idazoxan in Healthy Participants (clinicaltrials.gov) - P1 | N=110 | Not yet recruiting | Sponsor: Terran Biosciences Australia Pty Ltd

New P1 trial

Guanfacine inhibits interictal epileptiform events and sodium currents in prefrontal cortex pyramidal neurons. (PubMed, Pharmacol Rep) - "This study shows that guanfacine inhibits interictal discharges in cortical neurons independently of alpha-2A adrenergic receptors. This effect may be mediated by voltage-gated sodium currents. Inhibition of interictal activity by guanfacine may be of clinical importance because interictal events often occur in patients with ADHD and may contribute to symptoms of this disease."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Epilepsy • Psychiatry

Phenylephrine-Induced Contraction in Guinea Pig Thoracic Aorta Is Triggered by Stimulation of α-Adrenoceptors Functionally Coupled with Store-Operated Ca Channels and Voltage-Dependent Ca Channels. (PubMed, Biol Pharm Bull) - "We examined whether the α-adrenoceptor (AR), which shows low affinity (pA < 9) for prazosin (an α-AR antagonist) and high affinity (pA ≈ 10) for tamsulosin/silodosin (α-AR antagonists), is involved in phenylephrine-induced contractions in the guinea pig (GP) thoracic aorta (TA)...In contrast, phenylephrine-induced contractions were not substantially suppressed by L-765314 (an α-AR antagonist), BMY 7378 (an α-AR antagonist), yohimbine, and idazoxan (α-AR antagonists). Phenylephrine-induced contractions were markedly inhibited by YM-254890 (a Gq protein inhibitor) or removal of extracellular Ca, and partially inhibited by verapamil (a voltage-dependent Ca channel (VDCC) inhibitor)...Among the mRNA encoding α-ARs/SOCC-related molecules, α-AR (Adra1a)/Orai3, Orai1, and Stim2 were abundant in this tissue. In conclusion, phenylephrine-induced contractions in the GP TA can be triggered by stimulation of Gq protein-coupled α-AR, followed by activation of SOCCs and VDCCs."

Journal

Noradrenergic Modulation of Stress Resilience. (PubMed, Pharmacol Res) - "It has attracted increasing attention over the past decades with the revolution of modern neuroscience technologies. In this review article, we first briefly go over resilience-related concepts and introduce rodent paradigms for segregation of susceptibility and resilience, then highlight recent literature that identifies the neuronal and molecular substrates of active resilience in the locus coeruleus, and discuss possible future directions for resilience investigations."

Journal • Review • Mood Disorders

Development of novel non-opioid alpha-2 adrenergic receptor agonists for the treatment of pain (Neuroscience 2022) - "We observed that increasing doses of the GB-based, α₂-AR agonists were effective when delivered singly or in combination in reducing transient scratching and biting pain behaviors in the sub-acute SP assay. The efficacy of the GB-based compounds was inhibited by idazoxan but not naloxone co-administration, supporting action at α₂-AR and not opioid receptors. The GB-based compounds were also effective at reducing expression of pain behavior in acute (inflammatory, and chronic (low back pain, neuropathic pain) rodent models of pain."

Back Pain • CNS Disorders • Lumbar Back Pain • Musculoskeletal Pain • Neuralgia • Pain

Alpha-2A but not 2B/C noradrenergic receptors in ventral tegmental area regulate phasic dopamine release in nucleus accumbens core. (PubMed, Neuropharmacology) - "Intra-VTA microinfusion of idazoxan - a non-subtype-specific α-AR antagonist, as well as BRL-44408 - a selective α-AR antagonist, attenuated electrically-evoked DA in the NAc...Finally, we confirmed the presence of α-AR protein in the VTA using western blotting. In conclusion, these data specify α-, but not α- or α-AR as the receptor subtype controlling NA release in the VTA."

Journal • Anesthesia • CNS Disorders • Post-traumatic Stress Disorder

LX9211, a Novel Therapeutic Approach to Treatment of Neuropathic Pain (PAINWeek 2022) - "Combination studies of AAK1 inhibitors with opioid antagonist (naloxone) and alpha-2 adrenergic antagonists (yohimbine and idazoxan) in preclinical models of neuropathic pain were conducted. We have identified a novel target and an associated drug candidate for the treatment of neuropathic pain. The results from preclinical models have recently been bolstered by encouraging topline results from a Phase 2 clinical trial in patients who suffer with PDN and need better therapeutic options than those currently available. Learning Objectives: Upon completion, the participant will be able to describe a potential novel mechanism to treat neuropathic pain Upon completion, the participant will be able to describe a potential new treatment option for neuropathic pain Upon completion, the participant will be able to describe limitations of current standard of care for neuropathic pain"

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Neuralgia • Pain

Analgesic Effect of SH003 and Trichosanthes kirilowii Maximowicz in Paclitaxel-Induced Neuropathic Pain in Mice. (PubMed, Curr Issues Mol Biol) - "The effect of Tk was shown to be mediated by the spinal noradrenergic system as intrathecal pretreatment with α- and α-adrenergic-receptor antagonists (prazosin and idazoxan), but not 5-HT, and 5-HT-receptor antagonists (methysergide and MDL-72222) blocked the effect of Tk. Among the phytochemicals of Tk, cucurbitacin D was shown to play a major role, as 0.025 mg/kg (i.p.) of cucurbitacin D alleviated allodynia similar to 500 mg/kg of SH003. These results suggest that Tk should be considered when treating paclitaxel-induced neuropathic pain."

Journal • Preclinical • Neuralgia • Oncology • Pain • Peripheral Neuropathic Pain

Regional binding of [ H]-MK801 to NMDA receptors in young and aged rat brain membranes. (PubMed, FASEB J) - "We also have shown that the alpha-2 adrenergic receptors agonist clonidine decreases this glutamate-stimulated NE release in a concentration-dependent manner; while in contrast, blockade of these receptors with phentolamine, an alpha-1 and alpha-2 adrenergic receptor blocker, or with idazoxan, a selective alpha-2 receptor blocker, markedly potentiates glutamate-stimulated NE release in cortical brain slices (Aljohani et al., 2021b). Since aging has heterogeneous effects on NMDA receptors in different brain areas, we have now begun to examine [ H]-MK801 binding to NMDA receptors to compare changes in receptor density and responsiveness during aging in the cortex, hippocampus, striatum, and olfactory tubercle, as a possible mechanistic explanation for the changes in NE and DA release. The data from cortical membrane preparations suggest that young and old rats have similar NMDA receptor densities but may differ in their response to stimulation with glutamate/glycine."

Journal • Preclinical