idazoxan (RX 781094) / Houston Pharma - LARVOL DELTA

Phenylephrine per se or Combined with Pregabalin Ameliorates Mononeuropathic Pain in Rats. (PubMed, Pharmaceutics) - "In addition, in the mouse vas deferens, PE produced smooth muscle contraction in prazosin and idazoxan sensitive manner...Under isoflurane anesthesia, this combination was devoid of cardiovascular side effects attributed to systolic and diastolic blood pressure, mean arterial pressure, or heart rate. PGB induced motor dysfunction was not altered upon the combination with PE. These data suggest that PE in combination with PGB shows promise in preclinical settings; however, the necessity for further studies is paramount to detail the pharmacokinetic interactions involved."

Journal • Preclinical • Anesthesia • Cardiovascular • Neuralgia • Pain

Clonidine Inhibits Interictal-like Epileptiform Events in Prefrontal Cortex Pyramidal Neurons. (PubMed, Int J Mol Sci) - "In the constant presence of the alpha-2 adrenergic receptor antagonist idazoxan 20 µM in all solutions, clonidine 100 µM also inhibited the frequency of interictal-like epileptiform events. Blockade of NMDA currents and voltage-gated sodium currents likely contributed to the inhibition of epileptiform events exerted by clonidine. The potential translational relevance of the study is discussed."

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

A Study of Idazoxan in Healthy Participants (clinicaltrials.gov) - P1 | N=150 | Active, not recruiting | Sponsor: Terran Biosciences Australia Pty Ltd | Recruiting ➔ Active, not recruiting | Trial completion date: Mar 2024 ➔ Dec 2027 | Trial primary completion date: Mar 2024 ➔ Dec 2027

Enrollment closed • Trial completion date • Trial primary completion date

Dexmedetomidine preconditioning attenuates myocardial ischemia/reperfusion-induced arrhythmia in rats by inhibiting KATP Channels via imidazoline receptors: A combined animal and in vitro study. (PubMed, Eur J Pharmacol) - "The present study demonstrates that dexmedetomidine exerts antiarrhythmic effects, which are associated with the suppression of sarcolemmal KATP channel function and moderate prolongation of APD. Pharmacological evidence using receptor antagonists suggests that this novel action is likely mediated through imidazoline I1 receptor signaling rather than the classical α2-adrenoceptor pathway."

Journal • Preclinical • Cardiovascular • Myocardial Ischemia • Reperfusion Injury

A Novel Role of Dexmedetomidine in the Modulation of Morphine Reward Memory via Gamma-Aminobutyric Acid Transporter-1. (PubMed, Anesthesiology) - "Dex facilitates the extinction of morphine-associated reward memory by competitively inhibiting GAT1, enhancing VTA GABAergic inhibition, and normalizing NAc D1-MSN activity. These findings reveal a novel GAT1 dependent, α₂-independent mechanism by which Dex modulates opioid reward circuitry, highlighting its potential as a therapeutic agent for OUD."

Journal • Addiction (Opioid and Alcohol) • Substance Abuse

Efficacy and Spinal Noradrenergic Mechanisms of Contralateral Melittin Acupuncture Against Paclitaxel-Induced Peripheral Neuropathic Pain in Rats. (PubMed, J Pain Res) - "For neuropharmacological analysis, prazosin (an α1-adrenoceptor antagonist) or idazoxan (an α2-adrenoceptor antagonist) was administered before apitherapy (n=6/group). This modulation induced a significant reorganization of nociceptive processing within dorsal horn pain-transmitting neurons, leading to attenuated neuropathic signs in the contralateral limb of rats. Collectively, our behavioral and neurophysiological findings provide pre-clinical evidence supporting melittin-based pharmacoacupuncture as a potential therapy for paclitaxel-induced neuropathic pain."

Journal • Preclinical • Immunology • Neuralgia • Pain • Peripheral Neuropathic Pain

Social stress worsens colitis through β-adrenergic-driven oxidative stress in intestinal mucosal compartments. (PubMed, Brain Behav Immun) - "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). Apocynin mitigated stress-induced ROS/RNS production and body weight loss even prior to colitis onset, reduced colonic expression of key oxidative enzymes, especially DUOX2, and alleviated both chemically and infectious colitis severity. 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."

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

Clonidine-induced tension changes in guinea pig thoracic aorta: roles of α1L-adrenoceptors, L-type voltage-dependent Ca2+ channels, and K+ channels. (PubMed, J Pharmacol Sci) - "Clonidine alone produced little change in basal tension; however, in the presence of tetraethylammonium (TEA) or Ba2+, it elicited a pronounced contraction that was almost completely abolished by verapamil...The Ba2+-enhanced clonidine-evoked contraction was insensitive to the α2-adrenoceptor (AR) antagonist idazoxan but was competitively inhibited by the α1-AR antagonists prazosin and tamsulosin, yielding pA2 values of 8.26 and 9.92, respectively...These L-type VDCC-mediated responses are negatively regulated by Ba2+-sensitive K+ channels. In addition, clonidine itself appears to directly or indirectly activate Ba2+-sensitive K+ channels, thereby suppressing the α1L-AR-L-type VDCC functional coupling."

Journal

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