T-type calcium channels antagonists

Mibefradil is a tetralol derivative originally developed as an antagonist of T-type voltage-gated calcium (Ca2+ ) channels to treat hypertension when used at nanomolar dosage. More recently, its therapeutic application in hypertension has declined and has been instead repurposed as a treatment of cancer cell proliferation and solid tumor growth. Beyond its function as a Cav blocker, the micromolar concentration of mibefradil can stimulate a rise in [Ca2+ ]cyt although the mechanism is poorly known. The chanzyme TRPM7 (transient receptor potential melastanin 7), the release of intracellular Ca2+ pools, and Ca2+ influx by ORAI channels have been associated with the increase in [Ca2+ ]cyt triggered by mibefradil...

Autoimmune uveitis (AU) is a sight-threatening ocular inflammatory disorder, characterized by massive retinal vascular leakage and inflamed lesions with infiltration of the uveitogenic T cells in the retina and disorders of the T cell-related immune response in the system. Stimulation of TCRs can trigger calcium release and influx via Ca2+ channels and then transmit signals from the surface to the nucleus, which are important for energy metabolism, proliferation, activation, and differentiation. Inhibition of Ca2+ influx by pharmacological modulation of Ca2+ channels may suppress T cell function, representing a novel anti-inflammatory strategy in the treatment of AU...

The cation channel of sperm (CatSper) is the principal entry point for calcium in human spermatozoa and its proper function is essential for successful fertilization. As CatSper is potently activated by progesterone, we evaluated a range of steroids to define the structure-activity relationships for channel activation and found that CatSper is activated by a broad range of steroids with diverse structural modifications. By testing steroids that failed to elicit calcium influx as inhibitors of channel activation, we discovered that medroxyprogesterone acetate, levonorgestrel, and aldosterone inhibited calcium influx produced by progesterone, prostaglandin E1 , and the fungal natural product l -sirenin, but these steroidal inhibitors failed to prevent calcium influx in response to elevated K+ and pH...

BACKGROUND: Type-17 inflammation characterizes psoriasis, a chronic skin disease. As several inflammatory cytokines contribute to psoriasis pathogenesis, inhibiting the simultaneous production of these cytokines in Th17-cells may be beneficial in psoriasis. We found that Cav 1.4, encoded by CACNA1F, was the only Cav 1 calcium channel expressed in Th17-cells. OBJECTIVE: We investigated the role of Cav 1.4 expression in early Th17-activation events and effector functions, as well as its association with Th17 signature genes in lesional psoriatic (LP) skins...

Nicotine-withdrawal after daily exposure manifests somatic and affective symptom including a range of cognitive deficits. Earlier studies suggested participation of L-type calcium channels (LTCCs) in development of nicotine dependence and expression of withdrawal signs. An upsurge in Ca2+ -induced oxidative stress in brain underlies the biochemical events and behavioral signs of nicotine-withdrawal. The present study is aimed to explore the effects of lacidipine (LTCC antagonist) against nicotine-withdrawal...

Two scalable and efficient synthetic routes for the synthesis of a T-type calcium channel antagonist MK-8998 were developed from a simple pyridine building block. The key step to set the stereochemistry relied on either chiral rhodium catalyst-mediated asymmetric hydrogenation of an enamide or transamination of an arylketone that provided the corresponding product in high enantioselectivity and high yield.

The mitochondrial inhibitor 3-nitropropionic acid (3-NP) induces excitotoxicity. The authors hypothesized that CTK 01512-2, a recombinant peptide calcium channel N-type blocker, and the TRPA1 antagonist, could show neuroprotective effects. The male Wistar rats received 3-NP [25 mg/kg (i.p.) for 7 days], and a treatment of CTK 01512-2 was delivered intrathecally (i.t.), thrice a week. The neuroprotective effects were evaluated by [18 F]FDG MicroPET analysis. The CTK 01512-2 toxin was able to reestablish similar glucose uptakes on the control animals...

Huntington's disease (HD) is a fatal, hereditary neurodegenerative disorder that predominantly affects striatal medium-sized spiny neurons and cortical pyramidal neurons (CPNs). It has been proposed that perturbations in Ca2+ homeostasis could play a role in CPN alterations. To test this hypothesis, we used the R6/2 mouse model of juvenile HD at different stages of disease progression; presymptomatic, early symptomatic, and late symptomatic. We combined whole-cell patch clamp recordings of layer 2/3 CPNs with two-photon laser scanning microscopy to image somatic and dendritic Ca2+ transients associated with evoked action potentials (APs)...

Mineralocorticoid antagonists have been shown to be useful in the treatment of severe heart failure and may even save lives in this context. However, the reason for the beneficial action of these drugs, as well as the physiological role played by the cardiac mineralocorticoid receptor (MR), are still poorly understood. While the proinflammatory action of aldosterone on the heart and the resulting fibrosis partly explain the improvement due to the anti-mineralocorticoid therapy, the reduction in sudden death is probably related to a lower occurrence of ventricular arrhythmias...

The EGF receptor (EGFR) has been extensively studied in tumor biology and recently a role in cardiovascular pathophysiology was suggested. The mineralocorticoid receptor (MR) is an important effector of the renin-angiotensin-aldosterone-system and elicits pathophysiological effects in the cardiovascular system; however, the underlying molecular mechanisms are unclear. Our aim was to investigate the importance of EGFR for MR-mediated cardiovascular pathophysiology because MR is known to induce EGFR expression...

Subtypes (1-4) of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in the central and peripheral nervous systems, as well as the cells of smooth muscles in many organs. They mainly serve to regulate cellular excitability in these tissues. The HCN channel blocker ZD7288 has been shown to reduce apomorphine-induced conditioned taste aversion on saccharin preference in rats suggesting potential antinausea/antiemetic effects. Currently, in the least shew model of emesis we find that ZD7288 induces vomiting in a dose-dependent manner, with maximal efficacies of 100% at 1 mg/kg (i...

Pharmaceutical features of phenylalkylamine derivatives (PAAs) binding to calcium channels have been studied extensively in the past decades. Only a few PAAs have the binding specificity on calcium channels, for example, NNC 55-0396. Here, we created the homology models of human Cav 3.2, Cav 3.3 and use them as a receptor on the rigid docking tests. The nonspecific calcium channel blocker mibefradil showed inconsistent docking preference across four domains; however, NNC 55-0396 had a unique binding pattern on domain II specifically...

BACKGROUND AND PURPOSE: T-type voltage-gated calcium channels are an emerging potential therapeutic target for neurological disorders including epilepsy and pain. Inhibition of T-type channels reduces the excitability of peripheral nociceptive sensory neurons and reverses pain hypersensitivity in male rodent pain models. However, administration of peripherally restricted T-type antagonists has failed to show efficacy in multiple clinical and preclinical pain trials, suggesting that inhibition of peripheral T-type channels alone may be insufficient for pain relief...

Our previous studies have implicated CaV 3.2 isoform of T-type Ca2+ channels (T-channels) in the development of postsurgical pain. We have also previously established that different T-channel antagonists can alleviate in vivo postsurgical pain. Here we investigated the analgesic potential of another T-channel blocker and endogenous antioxidant molecule, α-lipoic acid (ALA), in a postsurgical pain model in rats. Our in vivo results suggest that single and repetitive intraperitoneal injections of ALA after surgery or preemptively, significantly reduced evoked mechanical hyperalgesia following surgical paw incision...

The suitability of a newly developed cell-based functional assay was tested for the detection of the activity of a range of neurotoxins and neuroactive pharmaceuticals which act by stimulation or inhibition of calcium-dependent neurotransmitter release. In this functional assay, a reporter enzyme is released concomitantly with the neurotransmitter from neurosecretory vesicles. The current study showed that the release of a luciferase from a differentiated human neuroblastoma-based reporter cell line (SIMA-hPOMC1-26-GLuc cells) can be stimulated by a carbachol-mediated activation of the Gq-coupled muscarinic-acetylcholine receptor and by the Ca2+ -channel forming spider toxin α-latrotoxin...

T-Type Ca2+ channels (T-channels), particularly Cav 3.2, are now considered as therapeutic targets for treatment of intractable pain including visceral pain. Among existing medicines, bepridil, a multi-channel blocker, used for treatment of arrhythmia and angina, and pimozide, a dopamine D2 receptor antagonist, known as a typical antipsychotic, have potent T-channel blocking activity. We thus tested whether bepridil and pimozide could suppress visceral pain in mice. Colonic and bladder pain were induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) and systemic administration of cyclophosphamide (CPA), respectively...

Studies have shown that in cancer cells, there is an increased T-type calcium channel (TTCC) expression compared to healthy cells. Therefore, the studies targeting TTCC for cancer therapy have shown many positive outcomes. Here, we have used TTA-A2- a potent TTCC inhibitor as a test drug, and paclitaxel (PTX)- a tubule-binding anti-cancer agent as a positive control. Blocking TTCC has shown to overcome resistance in cancer cells towards anti-cancer drugs by reducing calcium influx, and some studies have shown that PTX treatment also reduces the intracellular calcium signaling in cells...

The inferior colliculus (IC) is an auditory midbrain structure involved in processing biologically important temporal features of sounds. The responses of IC neurons to these temporal features reflect an interaction of synaptic inputs and neuronal biophysical properties. One striking biophysical property of IC neurons is the rebound depolarization produced following membrane hyperpolarization. To understand how the rebound depolarization is involved in spike timing, we made whole-cell patch clamp recordings from IC neurons in brain slices of P9-21 rats...

AIMS: Despite the advanced cancer treatments, there is increased resistance to chemotherapy and subsequent mortality. In lack of reliable data in monolayer cultures and animal models, researchers are shifting to 3D cancer spheroids, which represents the in vivo robust tumour morphology. Calcium is essential in cell signalling and proliferation. It is found that T-type calcium channels (TTCCs) are overexpressed in various cancer cells, supporting their increased proliferation. Many of the TTCCs blockers available could target other channels besides TTCCs, which can cause adverse effects...

OBJECTIVE: Ziconotide (ω-conotoxin MVIIA peptide) is a novel analgesic agent acting on voltage-gated calcium channels and is administered intrathecally for neuropathic pain. While antiepileptic activities of other types of calcium channel blockers (T- or L-type) are well established, there is no information regarding the effect of ziconotide as an N-type calcium channel antagonist in pentylenetetrazol-induced seizures or its anxiolytic and sedative activities. The present study is the first to report on these effects...