Browsing by Author "Majellaro, Maria"

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    Exploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonists
    (2023) Prieto-Diaz, Ruben; Gonzalez-Gomez, Manuel; Fojo-Carballo, Hugo; Azuaje, Jhonny; El Maatougui, Abdelaziz; Majellaro, Maria; Loza, Maria, I; Brea, Jose; Fernandez-Duenas, Victor; Paleo, M. Rita; Diaz-Holguin, Alejandro; Garcia-Pinel, Beatriz; Mallo-Abreu, Ana; Estevez, Juan C.; Andujar-Arias, Antonio; Garcia-Mera, Xerardo; Gomez-Tourino, Iria; Ciruela, Francisco; Salas, Cristian O.; Gutierrez-de-Teran, Hugo; Sotelo, Eddy
    The modulation of the A2B adenosine receptor is a promising strategy in cancer (immuno) therapy, with A2BAR antagonists emerging as immune checkpoint inhibitors. Herein, we report a systematic assessment of the impact of (di-and mono-)halogenation at positions 7 and/or 8 on both A2BAR affinity and pharmacokinetic properties of a collection of A2BAR antagonists and its study with structure-based free energy perturbation simulations. Monohalogenation at position 8 produced potent A2BAR ligands irrespective of the nature of the halogen. In contrast, halogenation at position 7 and dihalogenation produced a halogen-size-dependent decay in affinity. Eight novel A2BAR ligands exhibited remarkable affinity (Ki < 10 nM), exquisite subtype selectivity, and enantioselective recognition, with some eutomers eliciting sub-nanomolar affinity. The pharmacokinetic profile of representative derivatives showed enhanced solubility and microsomal stability. Finally, two compounds showed the capacity of reversing the antiproliferative effect of adenosine in activated primary human peripheral blood mononuclear cells.
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    Pharmacological insights emerging from the characterization of a large collection of synthetic cannabinoid receptor agonists designer drugs
    (2023) Gioe-Gallo, Claudia; Ortigueira, Sandra; Brea, Jose; Raich, Iu; Azuaje, Jhonny; Paleo, M. Rita; Majellaro, Maria; Loza, Maria Isabel; Salas, Cristian O.; Garcia-Mera, Xerardo; Navarro, Gemma; Sotelo, Eddy
    Synthetic cannabinoid receptor agonists (SCRAs) constitute the largest and most defiant group of abuse designer drugs. These new psychoactive substances (NPS), developed as unregulated alternatives to cannabis, have potent cannabimimetic effects and their use is usually associated with episodes of psychosis, seizures, dependence, organ toxicity and death. Due to their ever-changing structure, very limited or nil structural, pharmacological, and toxicological information is available to the scientific community and the law enforcement offices. Here we report the synthesis and pharmacological evaluation (binding and functional) of the largest and most diverse collection of enantiopure SCRAs published to date. Our results revealed novel SCRAs that could be (or may currently be) used as illegal psychoactive substances. We also report, for the first time, the cannabimimetic data of 32 novel SCRAs containing an (R) configuration at the stereogenic center. The systematic pharmacological profiling of the library enabled the identification of emerging Structure-Activity Relationship (SAR) and Structure-Selectivity Relationship (SSR) trends, the detection of ligands exhibiting incipient cannabinoid re-ceptor type 2 (CB2R) subtype selectivity and highlights the significant neurotoxicity of representative SCRAs on mouse primary neuronal cells. Several of the new emerging SCRAs are currently expected to have a rather limited potential for harm, as the evaluation of their pharmacological profiles revealed lower potencies and/or efficacies. Conceived as a resource to foster collaborative investigation of the physiological effects of SCRAs, the library obtained can contribute to addressing the challenge posed by recreational designer drugs.