The cannabinoid receptors (CB1/CB2) and the T-type calcium channels are involved in disorders associated with both physiological pain and depressive behaviors. Valuable pharmacological species carbazole derivatives such as the NMP-4, NMP-7, and NMP-181 (Neuro Molecular Production) regulate both biological entities. In this work, DFT calculations were performed to characterize theoretically their structural and chemical reactivity properties using the BP86/cc-pVTZ level of theory. The molecular orbital contributions and the chemical reactivity analysis reveal that a major participation of the carbazole group is in the donor-acceptor interactions of the NMP compounds. The DFT analysis on the NMP compounds provides insights into the relevant functional groups involved during the ligand-receptor interactions. Molecular docking analysis is used to reveal possible sites of interaction of the NMP compounds with the Cav3.2 calcium channel. The interaction energy values and reported experimental evidence indicate that the site denominated as \"Pore-blocking\", which is formed mainly by hydrophobic residues and the T586 residue, is a probable binding site for the NMP compounds.

1,4-Dihydropyridines (DHPs) are the most important class of L-type calcium channel blockers that are employed for the treatment of cardiovascular diseases, particularly hypertension. Various modifications on this scaffold lead to the discovery of new DHPs blocking different types of calcium channels. Among them, the T-type calcium channel has recently attracted great interest due to its role in chronic pain conditions. In this study, we selected three newly synthesized DHPs (HM8, HM10 and MD20) with different selectivity profiles to the T-type calcium channel and formulated them in micellar solutions and micellar-in-gel matrices to be tested for potential topical use in the treatment of neuropathic pain. To prevent the well-known sensitivity to light of the DHPs, the studied compounds were entrapped in colloidal aggregates obtained by using edible Pluronic® surfactants and adding α-tocopherol as an antioxidant. All the prepared formulations were exposed to stressing light, according to international rules. Along with the degradation experiments, the concentrations of the parent compounds and by-products were calculated by multivariate curve resolution-alternating least squares (MCR-ALS) applied to the spectral data. The defined formulations proved suitable as light-stable matrices for the DHP compounds, showing an increase in stability for HM8 and MD20 and an almost complete photoprotection for HM10, compared to ethanol solutions and standard gel formulations.

Early-onset severe spinocerebellar ataxia 42 with neurodevelopmental deficits (SCA42ND, MIM#604065) is an ultrarare autosomal dominant syndrome related to de novo CACNA1G gain-of-function pathogenic variants. All patients with SCA42ND show cerebellar atrophy and/or hypoplasia on neuroimaging and share common features such as dysmorphic features, global developmental delay, and axial hypotonia, all manifesting within the first year of life. To date, only 10 patients with SCA42ND have been reported with functionally confirmed gain-of-function variants, bearing either of two recurrent pathogenic variants. We describe a girl with congenital ataxia, without epilepsy, and a de novo p.Ala961Thr pathogenic variant in CACNA1G. We review the published subjects with the aim of better characterizing the dysmorphic features that may be crucial for clinical recognition of SCA42ND. Cerebellar atrophy, together with digital anomalies, particularly broad thumbs and/or halluces, should lead to clinical suspicion of this disease. We describe the first pharmacological attempt to treat a patient with SCA42ND using zonisamide, an antiepileptic drug with T-type channel blocker activity, in an off-label indication using an itemized study protocol. No efficacy was observed at the dose tested. However, without pharmacological treatment, she showed a positive evolution in neurodevelopment during the follow-up.

OBJECTIVE: We previously demonstrated that iron-overload in non-thalassemic rats induced neurotoxicity and cognitive decline. However, the effect of iron-overload on the brain of thalassemic condition has never been investigated. An iron chelator (deferiprone) provides neuroprotective effects against metal toxicity. Furthermore, a T-type calcium channels blocker (efonidipine) effectively attenuates cardiac dysfunction in thalassemic mice with iron-overload. However, the effects of both drugs on brain of iron-overload thalassemia has not been determined. We hypothesize that iron-overload induces neurotoxicity in Thalassemic and wild-type mice, and not only deferiprone, but also efonidipine, provides neuroprotection against iron-overload condition.
METHODS: Mice from both wild-type (WT) and β-thalassemic type (HT) groups were assigned to be fed with a standard-diet or high-iron diet containing 0.2% ferrocene/kg of diet (HFe) for 4 months consecutively. After three months of HFe, 75-mg/kg/d deferiprone or 4-mg/kg/d efonidipine were administered to the HFe-fed WT and HT mice for 1 month.
RESULTS: HFe consumption caused an equal impact on circulating iron-overload, oxidative stress, and inflammation in WT and HT mice. Brain iron-overload and iron-mediated neurotoxicity, such as oxidative stress, inflammation, glial activation, mitochondrial dysfunction, and Alzheimer\'s like pathologies, were observed to an equal degree in HFe fed WT and HT mice. These pathological conditions were mitigated by both deferiprone and efonidipine.
CONCLUSIONS: These findings indicate that iron-overload itself caused neurotoxicity, and T-type calcium channels may play a role in this condition.

Cardiovascular diseases (CVDs) are the main cause of deaths worldwide. Up-to-date, hypertension is the most significant contributing factor to CVDs. Recent clinical studies recommend calcium channel blockers (CCBs) as effective treatment alone or in combination with other medications. Being the most clinically useful CCBs, 1,4-dihydropyridines (DHPs) attracted great interest in improving potency and selectivity. However, the short plasma half-life which may be attributed to the metabolic oxidation to the pyridine-counterparts is considered as a major limitation for this class. Among the most efficient modifications of the DHP scaffold, is the introduction of biologically active N3-substituted dihydropyrimidine mimics (DHPMs). Again, some potent DHPMs showed only in vitro activity due to first pass effect through hydrolysis and removal of the N3-substitutions. Herein, the synthesis of new N3-substituted DHPMs with various functionalities linked to the DHPM core via two-carbon spacer to guard against possible metabolic inactivation is described. It was designed to keep close structural similarities to clinically efficient DHPs and the reported lead DHPMs analogues, while attempting to improve the pharmacokinetic properties through better metabolic stability. Applying whole batch clamp technique, five compounds showed promising L- and T- type calcium channel blocking activity and were identified as lead compounds. Structure requirements for selectivity against Cav1.2 as well against Cav3.2 are described.

Low-voltage-activated calcium channels are important regulators of neurotransmission and membrane ion conductance. A plethora of intracellular events rely on their modulation. Accordingly, they are implicated in many disorders including epilepsy, Parkinson\'s disease, pain and other neurological diseases. Among different subfamilies, T-type calcium channels, and in particular the CaV3.2 isoform, were shown to be involved in nociceptive neurotransmission. The role of CaV3.2 in pain modulation was supported by demonstrating selective antisense oligonucleotide-mediated CaV3.2 knockdown, in vivo antinociceptive effects of T-type blockers, and pain attenuation in CaV3.2 knockout formalin-induced pain model. These Emerging investigations have provided new insights into targeting T-type calcium channels for pain management. Within this scope, various T-type calcium channel blockers have been developed such as mibefradil and ethosuximide. Although being active, most of these molecules interact with other receptors as well. This addresses the need for T-selectivity. Few selective T-type channel blockers of diverse chemical classes were developed such as ABT-639 and TTA-P2. Interestingly, R(-) efonidipine which is a dihydropyridine (DHP) showed T-channel selectivity. Systematic modification of 1,4-dihydropyridine scaffold introduced novel derivatives with 40-fold T-type selectivity over L-type calcium channels. Along these lines, substitution of the DHP core with various analogues favored T-selectivity and may serve as novel pharmacophores. Several dihydropyrimidine (DHPM) mimics were introduced by Squibb as potential candidates. As a continuation of this approach, the current study describes the synthesis of Novel N3 substituted DHPMs with structure similarities to the active DHPs. Different functional groups were introduced to the N3 position through a spacer to gain more information about activity and selectivity. Furthermore, the spacer aims at improving the metabolic stability of the molecules. Initial screening data by whole patch clamp technique showed a robust inhibition of Cav3.2 T-type channels by eleven compounds. Interestingly, four compounds of these were efficient selective T-type blockers. Based on selectivity and efficiency, two compounds were selected for in vivo evaluation in mouse models of inflammatory pain. Results showed effective attenuation of nociception and mechanical hypersensitivity.