Z944 / Sun Pharma - LARVOL DELTA

Cav3.2 channels modulate allodynia but TRP channels are the primary mediators in prenatal valproic acid-induced sensory dysfunction. (PubMed, Neuroscience) - "A967079, ononetin, AMTB, gabapentin, and VPA reduced mechanical allodynia in 8-week-old pre-VPA males, while Z944 and II-2 were ineffective. Electrophysiology revealed normal rheobase but reduced firing frequency in DRG neurons from pre-VPA WT males, suggesting the possibility of central sensitization rather than peripheral hyperactivity. Our findings demonstrate that prenatal VPA induces mechanical and cold allodynia that is overcome by TRPA1, TRPM3, and TRPM8 blockers."

Journal • Autism Spectrum Disorder • Genetic Disorders • Pain • CAV3 • TRPA1 • TRPM3 • TRPM8 • TRPV1

Reticular thalamic hyperexcitability drives autism spectrum disorder behaviors in the Cntnap2 model of autism. (PubMed, Sci Adv) - "Notably, pharmacological and chemogenetic suppression of RT excitability via Z944, a T-type calcium channel blocker, and via C21 activation of the inhibitory DREADD hM4Di significantly improved ASD-related behaviors. These findings identify RT hyperexcitability as a mechanistic driver of ASD and highlight RT as a potential therapeutic target."

Journal • Autism Spectrum Disorder • CNS Disorders • Epilepsy • Genetic Disorders • Sleep Disorder

Functional expression of the T-type Cav3.2 calcium channel in female and male human dorsal root ganglion neurons. (PubMed, Brain) - "The Cav3.2 current exhibits typical biophysical and pharmacological properties, including inhibition by a low concentration of nickel and by Z944, a specific T-type calcium channel blocker in advanced clinical development. Conversely, ABT-639, a T-type calcium channel inhibitor that failed in Phase 2 trials for pain relief, does not inhibit Cav3.2 currents in human DRG neurons. Importantly, Cav3.2 currents are prominent in neurons from female organ donors, supporting the presence of sex differences in pain mechanisms in humans. These findings underscore the potential of continued exploration of Cav3.2 as a therapeutic target for pain treatment and highlight a specific subset of human neurons that likely rely on this channel to modulate their excitability."

Journal • Neuralgia • Pain • CACNA1H • CAV3 • NTRK2

Reticular Thalamic Hyperexcitability Drives Autism Spectrum Disorder Behaviors in the Cntnap2 Model of Autism. (PubMed, bioRxiv) - "Notably, suppressing RT activity via Z944, a T-type calcium channel blocker, and via C21 and the inhibitory DREADD hM4Di, improved ASD-related behavioral deficits. These findings identify RT hyperexcitability as a mechanistic driver of ASD behaviors and underscore RT as a potential therapeutic target for modulating thalamocortical circuit dysfunction in ASD. RT hyperexcitability drives ASD behaviors in Cntnap2-/- mice, highlighting RT as a therapeutic target for circuit dysfunction."

Journal • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Psychiatry • Sleep Disorder

Ganomycin C, a Ganoderma Meroterpenoid, Alleviates Pain and Absence Seizures in Mice by Targeting Cav3.1 and Cav3.2 Low-Voltage-Gated Calcium Channels. (PubMed, Phytother Res) - "In three of the pain models, GMC demonstrated robust antinociception comparable to that of Z944 and outperformed ethosuximide, a standard-of-care drug for ASs, in mitigating ASs. Our findings provide insights into GMC as an analgesic and anti-AS agent targeting LVGCCs, specifically Cav3.1 and Cav3.2."

Journal • Preclinical • Absence Seizure Disorder • CNS Disorders • Epilepsy • Pain • CAV3

COVID-19 AND SHORT-TERM MORTALITY IN NON-COVID-19 CRITICALLY ILL SOLID ORGAN TRANSPLANT PATIENTS (SCCM 2025) - "SOT was defined by ICD-10 codes Z940 (kidney), Z941 (heart), Z942 (lung), and Z944 (liver)... The COVID-19 pandemic was associated with an acute rise in short-term mortality among non-COVID-19 critically ill patients with SOT and it stalled their gradual pre-pandemic mortality downtrend."

Clinical • Infectious Disease • Novel Coronavirus Disease • Solid Organ Transplantation • Transplantation

CaV3.2 T-type calcium channels contribute to CGRP- induced allodynia in a rodent model of experimental migraine. (PubMed, J Headache Pain) - "The present study suggests that CGRP modulates CaV3.2 in the TG, an effect possibly mediated by the canonical CGRP receptor and PKA activation. The increase in T-type currents in the TG may represent a contributing factor for the initiation and maintenance of the headache pain during migraine."

Journal • Preclinical • CNS Disorders • Migraine • Pain • CALCRL • CAV3

Eco-Friendly Synthesis and Molecular Modelling of 2-Phenylimidazo[1,2-b]pyridazine Derivatives: In Vitro and In Vivo Studies for Lead Optimization. (PubMed, ChemMedChem) - "To lay the groundwork for the future rational optimization of this promising class of compounds, the molecular bases of DM1 and DM2 activity were investigated by modelling their interaction with hCav3.1 channels. The calculated binding modes of DM1 and DM2 to hCav3.1 channels partially mirrored that of the selective Cav3.1 blocker Z944, paving the way for future lead optimization."

Journal • Preclinical • Brain Cancer • CNS Disorders • CNS Tumor • Epilepsy • Glioma • Oncology • Solid Tumor • CAV3

Contribution of T-type calcium channel isoforms to cold and mechanical sensitivity in naïve and oxaliplatin-treated mice of both sexes. (PubMed, Br J Pharmacol) - "Altogether, our data indicate that T-type channels differentially contribute to the regulation of cold and mechanical hypersensitivity, and raise the possibility that T-type channel blockers could promote cold allodynia."

Journal • Preclinical • Immunology • Pain • Peripheral Neuropathic Pain • Targeted Protein Degradation • CAV3 • USP5

Burden and frequency of viral testing of kidney and non-kidney transplant recipients. (PubMed, Microbiol Spectr) - "We included 345 patients with International Classification of Diseases (ICD)-10 codes for transplant (Z940-Z942, Z944, Z9481, Z9483, Z9484) with at least two tests (within 7 days) in January 2019 and at least one test in December 2020 to find patients in the post-transplant period...The Organ Procurement and Transplant Network (OPTN) has developed a strategic plan to improve and standardize the transplant process in the US to improve outcomes of living donors and recipients. Publishing national reference lab data on the testing frequency and its alignment with the recommended guidelines for post-transplant infectious diseases can inform patient uptake and compliance for these strategic OPTN efforts."

Journal • Cytomegalovirus Infection • Epstein-Barr Virus Infections • Infectious Disease • Nephrology • Renal Disease • Transplantation

Effect of ABT-639 on Cav3.2 channel activity and its analgesic actions in mouse models of inflammatory and neuropathic pain. (PubMed, Eur J Pharmacol) - "In the CFA model, both compounds reversed thermal hyperalgesia upon systemic delivery, but only Z944 mediated pain relief upon intrathecal delivery, indicating that ABT-639 acts primarily at peripheral sites. ABT-639 lost its analgesic effects in CFA treated Cav3.2 null mice, indicating that these channels are essential for ABT-639-mediated pain relief despite its poor inhibition of Cav3.2 currents."

Journal • Preclinical • Immunology • Neuralgia • Pain • CAV3

Discovery of α-Obscurine Derivatives as Novel Cav3.1 Calcium Channel Blockers. (PubMed, Chem Biodivers) - "Despite the clinical trials of TTCC blockers like Z944 and MK8998, none are currently available on the market. The most potent derivative, compound 7, exhibited an IC50 value of 0.19 ± 0.03 μM and was further analyzed through molecular docking, revealing key interactions with Cav3.1. These findings provide a foundation for the structural optimization of Cav3.1 calcium channel blockers and present compound 7 as a promising lead compound for drug development and a tool for chemical biology research."

Journal • CNS Disorders • Epilepsy • Oncology • Pain • CAV3

Analgesic Buxus alkaloids with Enhanced Selectivity for the Low-Voltage-Gated Calcium Channel Cav3.2 over Cav3.1 through a New Binding Mode. (PubMed, Angew Chem Int Ed Engl) - "Animal studies in wild-type and Cav3.2 knock-out mice revealed that BXSL (5 mg/kg), by inhibiting Cav3.2, exhibits an analgesic effect equivalent to Z944 (10 mg/kg) or mibefradil (10 mg/kg). Moreover, we proposed a structural rationale for 9(10/19)abeo-artane-type alkaloids towards their high selectivity of Cav3.2 over Cav3.1. This study introduces a novel analgesic agent and valuable molecular insights for structure-based innovative Cav3.2 drug development."

Journal • CNS Disorders • Epilepsy • Essential Tremor • Movement Disorders • Pain • CAV3

Cav3.2 T-type calcium channels modulate dentate gyrus granule cell excitability in a maturational stage dependent manner (Neuroscience 2023) - "Similar results were found with acute pharmacological blockade of T-type calcium channels in WT using the T-type antagonist Z944...2 promotes the low intrinsic excitability of GCs. These findings might shed light on the development of acquired epilepsies such as epilepsy that develops after traumatic brain injury where this filtering function appears reduced."

CNS Disorders • Epilepsy • Vascular Neurology • CAV3

Englerin A inhibits T-type CaV channels at low-micromolar concentrations. (PubMed, Mol Pharmacol) - "While the T-type blocker Z944 reduced basal and angiotensin II-induced 24-hour aldosterone release, EA was not effective. In summary, we show here that EA blocks CaV1.2 and T-type CaV channels at low-micromolar concentrations. Significance Statement In this study we showed that englerin A (EA), a potent agonist of TRPC4- or TRPC5-containing tetrameric TRPC channels and currently under investigation to treat certain types of cancer, also inhibits L-type voltage-gated CaV1.2 and T-type voltage-gated CaV3.1, CaV3.2 and CaV3.3 Ca channels at low-micromolar concentrations."

Journal • Oncology • TRPC1

Effects of Potential Anti-epileptogenic Drugs on High Frequency Oscillations in the Fluid Percussion Injury Rat Model of Post-traumatic Epilepsy: An epibios4rx Project 2 Study from the Melbourne Site (AES 2022) - "LEV and sodium selenate both significantly reduced the numbers of fast ripples post-LFPI. Considering previous research has shown HFOs may be predictive of epileptogenesis in the LFPI rats, this effect of levetiracetam and sodium selenate to reduce fast ripples could be a biomarker of potential anti-epileptogenesis post-TBI in this model."

Preclinical • CNS Disorders • Epilepsy • Vascular Neurology

Mechanistic contribution of CaV3.2 calcium channels to trigeminal neuralgia pathophysiology not clarified. (PubMed, F1000Res) - "They used a infraorbital nerve constriction injury and measured facial heat hyperalgesia.  CaV3.2-/- show a pain phenotype similar to control, yet are not affected by a CaV3-inhibitory compound, Z944...Re thermal cue, Gambeta-et-al failed to study cold-evoked pain which is a TN clinical hallmark. Thus, Gambeta-et-al's 2022 PAIN-paper offers little new mechanistic evidence why CaV3.2 polymorphisms are associated with trigeminal neuralgia."

Journal • Neuralgia • Pain

Icetexane diterpenoids as Ca3.2 T-type calcium channel inhibitors from Salvia prattii and analgesic effect of their Semi-synthesized derivatives. (PubMed, Bioorg Chem) - "Significantly, they exhibited dose-dependent (1, 3, and 10 mg/kg) and comparable analgesic effects as that of Z944, a TTCCs inhibitor under clinical trial for pain management, in the mouse acetic acid writhing test. These findings further enrich structural diversity and bioactivity of Salvia diterpenoids, as well as provide promising structural templates for the development of Ca3.2 analgesics."

Journal • Pain

CaV3.2 calcium channels contribute to trigeminal neuralgia. (PubMed, Pain) - "Block of T-type channels with Z944 resulted in antihyperalgesia...Finally, ELISA analysis revealed increased CaV3.2 channel expression in the spinal trigeminal subnucleus caudalis. Altogether, the present study demonstrates an important role of CaV3.2 channels in trigeminal pain."

Journal • Neuralgia • Pain

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets. (PubMed, Front Pain Res (Lausanne)) - "Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing "pain" as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a..."

Journal • Review • Hematological Malignancies • Immunology • Inflammatory Arthritis • Lymphoma • Neuralgia • Oncology • Pain • Rheumatoid Arthritis • Rheumatology • T Cell Non-Hodgkin Lymphoma • TAP1

Discovery of novel coffee diterpenoids with inhibitions on Ca3.1 low voltage-gated Ca channel. (PubMed, Food Chem) - "Further studies indicated that 1 and cafestol may act on different binding sits with the Ca3.1 blocker Z944, which is in clinical trial. Significantly, the present study initially shows that coffee diterpenoids are potential natural resources for Ca3.1 inhibitors."

Journal

The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva). (PubMed, Front Pharmacol) - "To reveal its mechanism(s) of emetic action, we evaluated the efficacy of diverse antiemetics against ZD7288-evoked vomiting including the antagonists/inhibitors of: ERK1/2 (U0126), L-type Ca channel (nifedipine); store-operated Ca entry (MRS 1845); T-type Ca channel (Z944), IPR (2-APB), RyR receptor (dantrolene); the serotoninergic type 3 receptor (palonosetron); neurokinin 1 receptor (netupitant), dopamine type 2 receptor (sulpride), and the transient receptor potential vanilloid 1 receptor agonist, resiniferatoxin. In sum, ZD7288 has emetic potential mainly via central mechanisms, a process which involves Ca signaling and several emetic receptors. HCN channel blockers have been reported to have emetic potential in the clinic since they are currently used/investigated as therapeutic candidates for cancer therapy related- or unrelated-heart failure, pain, and cognitive impairment."

Journal • Alzheimer's Disease • Cardiovascular • Cognitive Disorders • Congestive Heart Failure • Heart Failure • Oncology • Pain • FOS

The T-type calcium channel antagonist, Z944, reduces spinal excitability and pain hypersensitivity. (PubMed, Br J Pharmacol) - "Our findings demonstrate that T-type calcium channels critically shape the excitability of lamina I pain processing neurons, and inhibition of these channels by the clinical stage antagonist Z944 potently reverses pain hypersensitivity across sexes."

Journal • CNS Disorders • Epilepsy • Immunology • Pain

Inhibitory Mechanism of the Isoflavone Derivative Genistein in the Human Ca3.3 Channel. (PubMed, ACS Chem Neurosci) - "Furthermore, our results from the unbiased MD simulations are in good agreement with the recently solved cryoelectron microscopy structure of the Ca3.1/Z944 complex in terms of both the location of the ligand binding site and the role of several equivalent amino acid residues...Specifically, we proposed that a combination of polar interactions involving the three hydroxyl groups of genistein and an aromatic interaction with the fused rings are the main binding interactions in the complex formation. Our results pave the way for the rational development of improved and novel low-voltage activated T-type calcium channel inhibitors."

Journal • CNS Disorders • Depression • Epilepsy • Mood Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain • Psychiatry

Disease-modifying effects of a novel T-type calcium channel antagonist, Z944, in a model of temporal lobe epilepsy. (PubMed, Prog Neurobiol) - "Animals were randomly assigned to one of 5 different groups: post-SE + Z944 (60 mg/kg/day, n = 8); post-SE + levetiracetam (200 mg/kg/day, n = 9); post-SE + vehicle (n = 8); sham + vehicle (n = 6) or sham + Z944 (60 mg/kg/day, n = 6). The results of this study show that treatment with Z944 has a disease-modifying effects in the post-SE model of TLE, reducing seizures as well as comorbid depressive-like behavior and cognitive impairment. This indicates that pharmacologically targeting T-type Ca channels may be an effective disease-modifying treatment for temporal lobe epilepsy."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Epilepsy • Mood Disorders