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7-methyl-2-phenylimidazo[1,2-b]pyridazin-3-carboxylic acid (DM1) and 6-methoxy-2-phenylimidazo[1,2-b]pyridazin-3-carboxylic acid (DM2) have been shown to act as human (h) Cav3.1 voltage-gated calcium channel blockers with promising in vivo anti-absence activity, positioning them as potential antiepileptic drugs. The primary aim of this work was to develop cost-effective and environmentally friendly synthetic procedures for preparing 2-phenylimidazo[1,2-b]pyridazine derivatives. After optimizing the synthesis of this compound class using efficient and green techniques such as microwaves and ultrasound irradiation, we further evaluated the antiepileptic effects of DM1 and DM2 in two animal models: CD-1 ICR mice after pentylenetetrazol administration and DBA/2 mice with seizures induced by audiogenic stimuli. Their neuroprotective effect against oxidative stress were assessed using C6 rat brain glioma cells. DM1 and DM2 exhibited potent anti-seizure effects in both animal models and demonstrated significant in vitro neuroprotective activity by reducing reactive oxygen species release. 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., (© 2024 Wiley‐VCH GmbH.)

Due to the neuroprotective role of the Na + /Ca 2+ exchanger (NCX) isoforms NCX1 and NCX3, we synthesized novel benzodiazepinone derivatives of the unique NCX activator Neurounina-1 , named compounds 1-19 . The derivatives are characterized by a benzodiazepinonic nucleus linked to five- or six-membered cyclic amines via a methylene, ethylene, or acetyl spacer. The compounds have been screened on NCX1/NCX3 isoform activities by a high-throughput screening approach, and the most promising were characterized by patch-clamp electrophysiology and Fura-2AM video imaging. We identified two novel modulators of NCX: compound 4 , inhibiting NCX1 reverse mode, and compound 14 , enhancing NCX1 and NCX3 activity. Compound 1 displayed neuroprotection in two preclinical models of brain ischemia. The analysis of the conformational and steric features led to the identification of the molecular volume required for selective NCX1 activation for mixed NCX1/NCX3 activation or for NCX1 inhibition, providing the first prototypal model for the design of optimized isoform modulators.

Introduction: Hydrogen sulfide (H 2 S) is a fundamental biological endogenous gas-mediator in the respiratory system. It regulates pivotal patho-physiological processes such as oxidative stress, pulmonary circulation, airway tone and inflammation., Objectives: We herein describe the design and synthesis of molecular hybrids obtained by the condensation of several corticosteroids with different hydrogen sulfide releasing moieties., Methods: All the molecules are characterized for their ability to release H 2 S both via amperometric approach and using a fluorescent probe. The chemical stability of the newly synthesized hybrid molecules has been investigated at differing pH values and in human serum., Results: Prednisone-TBZ hybrid (compound 7 ) was selected for further evaluations. The obtained results from the in vitro and in vivo studies clearly show evidence in favor of the anti-inflammatory properties of the released H 2 S., Conclusions: The protective effect on airway remodeling makes the hybrid Prednisone-TBZ (compound 7 ) as a promising therapeutic option in reducing allergic asthma symptoms and exacerbations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University.)

Introduction: The gasotransmitter hydrogen sulphide (H 2 S), an endogenous ubiquitous signalling molecule, is known for its beneficial effects on different mammalian systems. H 2 S exhibits cardioprotective activity against ischemia/reperfusion (I/R) or hypoxic injury., Methods: A library of forty-five isothiocyanates, selected for their different chemical properties, has been evaluated for its hydrogen sulfide (H 2 S) releasing capacity. The obtained results allowed to correlate several factors such as steric hindrance, electronic effects and position of the substituents to the observed H 2 S production. Moreover, the chemical-physical profiles of the selected compounds have been studied by an in silico approach and from a combination of the obtained results, 3-pyridyl-isothiocyanate (25) has been selected as the most promising one. A detailed pharmacological characterization of its cardioprotective action has been performed., Results: The results herein obtained strongly indicate 3-pyridyl-isothiocyanate (25) as a suitable pharmacological option in anti-ischemic therapy. The cardioprotective effects of compound 25 were tested in vivo and found to exhibit a positive effect., Conclusion: Results strongly suggest that isothiocyanate-based H 2 S-releasing drugs, such as compound 25, can trigger a ''pharmacological pre-conditioning" and could represent a suitable pharmacological option in antiischemic therapy., Competing Interests: The authors have declared no conflict of interest., (© 2020 The Authors. Published by Elsevier B.V. on behalf of Cairo University.)

The serotonin receptor subtype 5-HT(1A) was one of the first serotonin receptor subtypes pharmacologically characterized. This receptor subtype has long been object of intense research and is implicated in the pathogenesis and treatment of anxiety and depressive disorders. In recent years, new chemical entities targeting the 5-HT(1A) receptor (alone or in combination with other molecular targets) have been proposed for novel therapeutic uses in neuroprotection, cognitive impairment, Parkinson's disease, pain treatment, malignant carcinoid syndrome, and prostate cancer. This Perspective compares existing data on expression and signaling activity of the 5-HT(1A) receptor to a ligand with an intrinsic agonist or antagonist profile. Our purpose is also to make a complete overview, useful for underlining the features needed to select a specific pharmacological profile rather than another one. This aspect could be really interesting to consider and justify the 5-HT(1A) receptor as a new attractive target for drug discovery.

This paper reports the microwave-assisted synthesis and the binding assays on the 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors of new benzotriazinone derivatives, in order to identify selective ligands for the 5-HT(1A) subtype receptor. Conventional and microwave heating of the reactions were compared. Good yields and short reaction times are the main advantages of our synthetic route. More active compounds were selected and further evaluated for their binding affinities on D(1), D(2) dopaminergic and alpha(1), alpha(2) adrenergic receptors. The 3-(2-(4-(naphthalen-1-yl)piperazin-1-yl)ethyl)benzo[d][1,2,3]triazin-4(3H)-one 5 with K(i)= 0.000178 nM was the most active and selective derivative for the 5-HT(1A)receptor with respect to other serotonin receptors and the most selective derivative compared to dopaminergic and adrenergic receptors.