| 1. |
- Jacome, Cristina, et al.
(author)
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Feasibility and Acceptability of an Asthma App to Monitor Medication Adherence : Mixed Methods Study
- 2021
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In: JMIR mhealth and uhealth. - : JMIR Publications. - 2291-5222. ; 9:5
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Journal article (peer-reviewed)abstract
- Background: Poor medication adherence is a major challenge in asthma, and objective assessment of inhaler adherence is needed. The InspirerMundi app aims to monitor adherence while providing a positive experience through gamification and social support. Objective: This study aimed to evaluate the feasibility and acceptability of the InspirerMundi app to monitor medication adherence in adolescents and adults with persistent asthma (treated with daily inhaled medication). Methods: A 1-month mixed method multicenter observational study was conducted in 26 secondary care centers from Portugal and Spain. During an initial face-to-face visit, physicians reported patients' asthma therapeutic plan in a structured questionnaire. During the visits, patients were invited to use the app daily to register their asthma medication intakes. A scheduled intake was considered taken when patients registered the intake (inhaler, blister, or other drug formulation) by using the image-based medication detection tool. At 1 month, patients were interviewed by phone, and app satisfaction was assessed on a 1 (low) to 5 (high) scale. Patients were also asked to point out the most and least preferred app features and make suggestions for future app improvements. Results: A total of 107 patients (median 27 [P25-P75 14-40] years) were invited, 92.5% (99/107) installed the app, and 73.8% (79/107) completed the 1-month interview. Patients interacted with the app a median of 9 (P25-P75 1-24) days. At least one medication was registered in the app by 78% (77/99) of patients. A total of 53% (52/99) of participants registered all prescribed inhalers, and 34% (34/99) registered the complete asthma therapeutic plan. Median medication adherence was 75% (P25-P75 25%-90%) for inhalers and 82% (P25-P75 50%-94%) for other drug formulations. Patients were globally satisfied with the app, with 75% (59/79) scoring >= 4,; adherence monitoring, symptom monitoring, and gamification features being the most highly scored components; and the medication detection tool among the lowest scored. A total of 53% (42/79) of the patients stated that the app had motivated them to improve adherence to inhaled medication and 77% (61/79) would recommend the app to other patients. Patient feedback was reflected in 4 major themes: medication-related features (67/79, 85%), gamification and social network (33/79, 42%), symptom monitoring and physician communication (21/79, 27%), and other aspects (16/79, 20%). Conclusions: The InspirerMundi app was feasible and acceptable to monitor medication adherence in patients with asthma. Based on patient feedback and to increase the registering of medications, the therapeutic plan registration and medication detection tool were redesigned. Our results highlight the importance of patient participation to produce a patient-centered and engaging mHealth asthma app.
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| 2. |
- Varin, Thibault, et al.
(author)
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Phe369(7.38) at human 5-HT7 receptors confers interspecies selectivity to antagonists and partial agonists
- 2010
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 159:5, s. 1069-1081
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Journal article (peer-reviewed)abstract
- Background and purpose: Human and rat 5-HT7 receptors were studied with a particular emphasis on the molecular interactions involved in ligand binding, searching for an explanation to the interspecies selectivity observed for a set of compounds. We performed affinity studies, molecular modelling and site-directed mutagenesis, with special focus on residue Phe(7.38) of the human 5-HT7 receptor [Cys(7.38) in rat]. Experimental approach: Competition binding studies were performed for seven 5-HT7 receptor ligands at three different 5-HT7 receptors. The functional behaviour was evaluated by measuring 5-carboxytryptamine-stimulated cAMP production. Computational simulations were carried out to explore the structural bases in ligand binding observed for these compounds. Key results: Competition experiments showed a remarkable selectivity for the human receptor when compared with the rat receptor. These results indicate that mutating Cys to Phe at position 7.38 profoundly affects the binding affinities at the 5-HT7 receptor. Computational simulations provide a structural interpretation for this key finding. Pharmacological characterization of compounds mr25020, mr25040 and mr25053 revealed a competitive antagonistic behaviour. Compounds mr22423, mr22433, mr23284 and mr25052 behaved as partial agonists. Conclusions and implications: We propose that the interspecies difference in binding affinities observed for the compounds at human and rat 5-HT7 receptors is due to the nature of the residue at position 7.38. Our molecular modelling simulations suggest that Phe(7.38) in the human receptor is integrated in the hydrophobic pocket in the central part of the binding site [Phe(6.51)-Phe(6.52)] and allows a tighter binding of the ligands when compared with the rat receptor.
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| 3. |
- Areias, Filipe, et al.
(author)
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2-Aryladenine Derivatives as a Potent Scaffold for Adenosine Receptor Antagonists : The 6-Morpholino Derivatives
- 2024
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In: Molecules. - : MDPI. - 1431-5157 .- 1420-3049. ; 29:11
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Journal article (peer-reviewed)abstract
- A set of 2-aryl-9-H or methyl-6-morpholinopurine derivatives were synthesized and assayed through radioligand binding tests at human A1, A2A, A2B, and A3 adenosine receptor subtypes. Eleven purines showed potent antagonism at A1, A3, dual A1/A2A, A1/A2B, or A1/A3 adenosine receptors. Additionally, three compounds showed high affinity without selectivity for any specific adenosine receptor. The structure-activity relationships were made for this group of new compounds. The 9-methylpurine derivatives were generally less potent but more selective, and the 9H-purine derivatives were more potent but less selective. These compounds can be an important source of new biochemical tools and/or pharmacological drugs.
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| 4. |
- Azuaje, Jhonny, et al.
(author)
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Effect of Nitrogen Atom Substitution in A(3) Adenosine Receptor Binding : N-(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists
- 2017
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 60:17, s. 7502-7511
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Journal article (peer-reviewed)abstract
- We report the first family of 2-acetamidopyridines as potent and selective A, adenosine receptor (AR) antagonists. The computer -assisted design was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. Some of the generated 2-acetamidopyridines elicit an antagonistic effect with excellent affinity (K-j < 10 nM) and outstanding selectivity profiles, providing an alternative and simpler chemical scaffold to the parent series of diarylpyrimidines. In addition, using molecular dynamics and free energy perturbation simulations, we elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which is revealed as a stabilizer of a water network in the binding site. The discovery of 2,6-diaryl-2-acetamidopyridines represents a step forward in the search of chemically simple, potent, and selective antagonists for the hA(3)AR, and exemplifies the benefits of a joint theoretical- experimental approach to identify novel hA(3)AR antagonists through succinct and efficient synthetic methodologies.
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| 5. |
- Ballante, Flavio, et al.
(author)
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Docking Finds GPCR Ligands in Dark Chemical Matter
- 2020
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 63:2, s. 613-620
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Journal article (peer-reviewed)abstract
- High-throughput screening has revealed dark chemical matter, a set of drug-like compounds that has never shown bioactivity despite being extensively assayed. If dark molecules are found active at a therapeutic target, their extraordinary selectivity profiles make excellent starting points for drug development. We explored if ligands of therapeutically relevant G-protein-coupled receptors could be discovered by structure-based virtual screening of the dark chemical matter. Molecular docking screens against crystal structures of the A(2A) adenosine and the D-4 dopamine receptors were carried out, and 53 top-ranked molecules were evaluated experimentally. Two ligands of each receptor were discovered, and the most potent had sub-micromolar affinities. Analysis of bioactivity data showed that the ligands lacked activity at hundreds of off-targets, including several that are associated with adverse effects. Our results demonstrate that virtual screening provides an efficient means to mine the dark chemical space, which could contribute to development of drugs with improved safety profiles.
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| 6. |
- Brea, Oriana, et al.
(author)
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Are beryllium-containing biphenyl derivatives efficient anion sponges?
- 2018
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In: Journal of Molecular Modeling. - : Springer Science and Business Media LLC. - 1610-2940 .- 0948-5023. ; 24:1
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Journal article (peer-reviewed)abstract
- The structures and stabilities of 2,2'-diBeX-1,1'-biphenyl (X = H, F, Cl, CN) derivatives and their affinities for F-, Cl-, and CN- were theoretically investigated using a B3LYP/6-311 + G(3df, 2p)//B3LYP/6-31 + G(d,p) model. The results obtained show that the 2,2'-diBeX-1,1'-biphenyl derivatives (X = H, F, Cl, CN) exhibit very high F-, Cl-, and CN- affinities, albeit lower than those reported before for their 1,8-diBeX-naphthalene analogs, in spite of the fact that the biphenyl derivatives are more flexible than their naphthalene counterparts. Nevertheless, some of the biphenyl derivatives investigated are predicted to have anion affinities larger than those measured for SbF5, which is considered one of the strongest anion capturers. Therefore, although weaker than their naphthalene analogs, the 2,2'-diBeX-1,1'-biphenyl derivatives can still be considered powerful anion sponges. This study supports the idea that compounds containing -BeX groups in chelating positions behave as anion sponges due to the electron-deficient nature and consequently high intrinsic Lewis acidity of these groups.
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| 7. |
- Carbajales, Carlos, et al.
(author)
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Enantiospecific Recognition at the A(2B) Adenosine Receptor by Alkyl 2-Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates
- 2017
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 60:8, s. 3372-3382
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Journal article (peer-reviewed)abstract
- A novel family of structurally simple, potent, and selective nonxanthine A(2B)AR ligands was identified, and its antagonistic behavior confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (16) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (16) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(+/-)16b, K-i = 24.3 nM] was resolved into its two enantiomers by chiral HPLC, and the absolute configuration was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at A(2B)AR, with the (S)-16b enantiomer retaining all the affinity (K-i = 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A(2B) adenosine receptor and opens new possibilities in ligand design for this receptor.
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| 8. |
- Crespo, Abel, et al.
(author)
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Discovery of 3,4-Dihydropyrimidin-2(1H)-ones As a Novel Class of Potent and Selective A(2B) Adenosine Receptor Antagonists
- 2013
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In: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 4:11, s. 1031-1036
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Journal article (peer-reviewed)abstract
- We describe the discovery and optimization of 3,4-dihydropyrimidin-2(1H)-ones as a novel family of (nonzanthine) A(2B) receptor antagonists that exhibit an unusually high selectivity profile. The Biginelli-based hit optimization process enabled a thoughtful exploration of the structure-activity and structure-selectivity relationships for this chemotype, enabling the identification of ligands that combine structural simplicity with excellent hA(2B) AdoR affinity and remarkable selectivity profiles.
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| 9. |
- Crespo, Abel, et al.
(author)
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Exploring the influence of the substituent at position 4 in a series of 3,4-dihydropyrimidin-2(1H)-one A(2B) adenosine receptor antagonists
- 2017
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In: Chemistry of Heterocyclic Compounds. - : Springer. - 0009-3122 .- 1573-8353. ; 53:3, s. 316-321
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Journal article (peer-reviewed)abstract
- In the context of a program to identify selective adenosine A(2B) receptor antagonists, we have obtained a focused library of 4-substituted 3,4-dihydropyrimidin-2(1H)-ones and its affinity for the four human adenosine receptor subtypes was determined. The synthesis was accomplished by using an experimentally simple and efficient Biginelli approach. The biological evaluation of the library revealed that all the documented derivatives exhibit low or negligible affinity for the A(2B) receptor, thus highlighting the critical importance of the substituent at position 4 of the 3,4-dihydropyrimidin-2(1H)-one chemotype.
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| 10. |
- El Maatougui, Abdelaziz, et al.
(author)
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3-Oxopyridazin-5-yl-Chalcone Hybrids : Potent Antiplatelet Agents That Prevent Glycoprotein IIb/IIIa Activation
- 2017
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In: CHEMISTRYSELECT. - : Wiley. - 2365-6549. ; 2:17, s. 4920-4933
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Journal article (peer-reviewed)abstract
- A novel family of potent and broad-spectrum antiplatelet agents has been discovered by exploration of a library of 3-oxopyridazin-5-yl-chalcone hybrids. The pharmacological evaluation of the collection established the most salient features of the SAR in this series and allowed the identification of lead compounds that exhibit antiplatelet activity that is substantially superior to drugs in clinical use and 3,4-methylenedioxy-β-nitrostyrene (MNS). The derivatives reported herein act on GPIIb/IIIa, but in a different manner to classical antagonists (e.g., tirofiban), by preventing GPIIb/IIIa activation. Given their mechanism of action, these compounds might avoid the adverse effects of antagonists (paradoxical GPIIb/IIIa activation) and constitute attractive pharmacological tools for the development of tailored agents for the treatment of platelet-dependent thrombosis.
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