Carmen Escolano

The imidazoline receptor (IR) system, comprising the I ₁ R, I ₂ R, and I ₃ R subtypes, consists of binding sites involved in cardiovascular, metabolic, and neurological disorders. This review updates the 2004 compilation by Dardonville and Rozas on IR ligands, emphasizing promising ligands, subtype selectivity, and pharmacological profiling. Representative ligands for each subtype are analyzed to highlight key pharmacological aspects, including affinity, selectivity, and functional activity, integrating findings from preclinical and clinical studies. Critical molecular targets such as Nischarin/IRAS for I ₁ R and MAO‐B–associated sites for I ₂ R are discussed in the context of ligand design and CNS penetration. I ₁ R‐selective ligands, exemplified by rilmenidine, show improved selectivity over α ₂ ‐adrenoceptors and exhibit antihypertensive, metabolic, and neuroprotective effects. I ₂ R ligands display neuroprotective, anti‐inflammatory, and analgesic activities, with CR4056 progressing to Phase II trials. PET imaging with [ ¹¹ C]BU99008 has validated I ₂ R upregulation as a biomarker for neurodegeneration. Overall, the IR system presents therapeutic opportunities: I ₁ R for cardiovascular and metabolic disorders, I ₂ R for pain and neurodegeneration, and I ₃ R for diabetes. Continued ligand optimization and receptor characterization are essential for clinical translation.

Neurodegenerative diseases such as Alzheimer’s (AD) and Huntington’s (HD) remain major therapeutic challenges due to limited treatment efficacy. Imidazoline I2 receptor (I2-IR) ligands have recently emerged as promising neuroprotective agents, with reported roles in modulating oxidative stress, neuroinflammation, and protein aggregation. This study evaluates the therapeutic potential of several I2-IR ligands, including Idazoxan, CR4056, and novel compounds, using Caenorhabditis elegans (C. elegans) models of AD and HD. Transgenic strains CL2006 (expressing human Aβ1-42) and EAK103 (expressing Ht513) were employed to assess locomotor activity, oxidative stress tolerance, Aβ and Ht aggregation, and sod-1 gene expression. Several ligands significantly improved movement, reduced Aβ and Ht aggregates, and enhanced antioxidant gene expression, particularly Idazoxan, LSL42, and PIP01. Notably, some compounds exhibited prooxidant effects, highlighting the utility of C. elegans for early in vivo toxicity screening. Importantly, this study provides the first in vivo evidence of the efficacy of I2-IR ligands in HD models and reinforces their potential as therapeutic candidates for HD. Overall, these findings suggest a potential role for modulation of I2-IR-related pathways in neurodegeneration and support the utility of C. elegans as a rapid, cost-effective platform for preclinical drug evaluation.

Background The synthesis of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates provided novel compounds with relevant affinities for imidazoline 2 (I2) receptors in human brain tissues. A selected compound, 12d, showed improved cognitive and analgesic properties at the preclinical level through the modulation of I2 receptors, but its potential innovative use as an antidepressant is still unknown. Methods Male and female adult Sprague-Dawley rats were treated with 3 ip injections of compound 12d (10 or 20 mg/kg), or vehicle (1 ml/kg DMSO), 24, 5, and 1 h prior to scoring its antidepressant-like efficacy under the stress of the forced-swim test. Hippocampal neuroplasticity markers (i.e., FADD, p-ERK/ERK, mBDNF) were evaluated 24 h post-treatment (and post-forced-swim test exposure). Results The novel results proved a sex-dependent efficacy of 12d, with dose-dependent antidepressant-like effects in adult male rats, and an inefficacious response for females. Moreover, compound 12d did not alter any of the hippocampal markers evaluated. Conclusions These results presented 12d as a novel therapeutic antidepressant candidate at the tested conditions, although only for male rats, thus requiring further studies to better understand the observed sex disparities as well as its molecular underpinnings. Moreover, compound 12d joins the list of other I2 receptor ligands with known antidepressant-like efficacy, validating and strengthening this receptor as a target in this field for future drug development.

The etiology of Alzheimer's disease (AD) is complex and multifactorial. There is a pressing need for therapies that can prevent or slow AD progression. Consequently, drug development has shifted from single‐target approaches to multi‐faceted strategies that emphasize early intervention rather than late‐stage treatment. One promising target is glycogen synthase kinase‐3β (GSK‐3β), an enzyme implicated in tau hyperphosphorylation and Aβ plaque formation. Based on our earlier work, we synthesized 25 2‐thioxo‐1,2,3,4‐tetrahydropyrimidine derivatives designed as GSK‐3β inhibitors, tau phosphorylation inhibitors, and Aβ accumulation. Two compounds emerged as particularly effective: compound 63 (IC₅₀ = 1.69 µM) and compound 66 (IC₅₀ = 0.90 µM), with compound 66 identified as an ATP‐competitive inhibitor of GSK‐3β. Further pharmacokinetic studies and in vitro drug metabolism assessments were conducted, followed by in vivo efficacy studies using Caenorhabditis elegans. Notably, these compounds reduced phosphorylated tau levels in the BR5706 strain and decreased Aβ aggregate deposition in the CL2006 strain. Molecular Dynamic (MD) simulations were also performed on both compounds. These findings provide valuable insights into GSK‐3β drug development and highlight the potential of these inhibitors as therapeutic candidates for AD by targeting both tau and Aβ, the two pathological hallmarks of AD.

Imidazoline I₂ receptors (I₂-IR) are untapped therapeutic targets lacking a structural description. Although the levels of I₂-IR are dysregulated in a plethora of illnesses, the arsenal of ligands that can modulate I₂-IR is limited. In this framework, we have reported several new structural families embodying the iminophosphonate functional group that have an excellent affinity and selectivity for I₂-IR, and selected members have demonstrated relevant pharmacological properties in murine models of neurodegeneration and Alzheimer’s disease. Starting with these iminophosphonates, we continued to exploit their high degree of functionalization through a short and efficient synthesis to access unprecedented 2,3-di, 2,2,3-tri, 2,3,4-tri, and 2,2,3,4-tetrasubstituted diethyl (pyrrolidine-2-yl) phosphonates. The stereochemistry of the new compounds was unequivocally characterized by X-ray crystallographic analyses. Two selected compounds with structural features shared with the starting products were pharmacologically evaluated, allowing us to deduce the required key structural motifs for biologically active aminophosphonate derivatives.

Imidazoline I 2 receptors (I2-IRs) are altered in Alzheimer's disease (AD) patients and are associated with analgesia. I2-IRs are not structurally described, and their pharmacological characterization relies on their modulation by highly affine ligands. Herein, we describe the synthesis of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates endowed with relevant affinities for I2-IRs in human brain tissues. The optimal ADME and pharmacokinetic profile of a selected compound, 12d, secured its in vivo exploration in a senescence accelerated prone 8 mice revealing improvement in the cognitive impairment and unveiling the mechanism of action by analyzing specific AD biomarkers. The treatment of a capsaicin-induced mechanical hypersensitivity murine model with 12d revealed analgesic properties devoid of motor coordination issues. The target engagement of 12d was demonstrated by suppression of the analgesic effect by pretreatment with idazoxan. Overall, 12d is a putative candidate for advancing preclinical phases and supports the modulation of I2-IRs as an innovative approach for therapeutics.

INTRODUCCIÓN. Desde 2015, la Facultad de Farmacia y Ciencias de la Alimentación de la Universidad de Barcelona implementa el programa «Pasaporte a la profesión» para vincular la formación académica del alumnado del grado de Farmacia con el mundo laboral. Este programa enfatiza la experiencia práctica y el desarrollo profesional mediante actividades, a fin de mejorar las oportunidades laborales de los estudiantes y prepararlos para los desafíos profesionales. En este artículo se analiza el progreso, la eficacia, el impacto del programa y sus áreas de mejora. MÉTODO. Se hizo un análisis comparativo utilizando las encuestas de satisfacción recopiladas entre los años 2015 y 2023. El estudio incluyó los datos sobre la evolución de la participación de los estudiantes, la evaluación de las sesiones y la identificación de puntos débiles del programa, entre otros parámetros. RESULTADOS y DISCUSIÓN. Destaca la alta valoración del programa por parte de los participantes, siendo necesarias mejoras en su difusión y en algunas áreas de contenidos. En consecuencia, se ha creado una hoja de ruta para el «Pasaporte a la profesión» con la intención de conseguir que el programa cumpla y supere sus objetivos educativos, adaptándose a las necesidades cambiantes de los estudiantes y del mercado laboral.

Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer’s disease (AD) being the most dominant, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I₂ receptors (I₂-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I₂-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I₂-IRs, the brain penetration capabilities, the in silico ADMET studies, and the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of this new bunch of I₂-IR ligands. Selected compounds showed neuroprotective properties and beneficial effects in an in vitro model of Parkinson’s disease, rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine, and showed crucial anti-inflammatory effects in a cellular model of neuroinflammation. After a preliminary pharmacokinetic study, we explored the action of our representative 2-(benzo[b]thiophen-2-yl)-1H-imidazole LSL33 in a mouse model of AD (5xFAD). Oral administration of LSL33 at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment and synaptic plasticity, as well as reduced neuroinflammation markers. In summary, this new I₂-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration.

Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, BC1618. This molecule showed a better potency than metformin, increasing GDF15 mRNA levels in human Huh-7 hepatic cells. Based on BC1618, structural modifications have been performed to create a collection of diversely substituted new molecules. Of the thirty-five new compounds evaluated, compound 21 showed a higher increase in GDF15 mRNA levels compared with BC1618. Metformin, BC1618, and compound 21 increased phosphorylated AMPK, but only 21 increased GDF15 protein levels. Overall, these findings indicate that 21 has a unique capacity to increase GDF15 protein levels in human hepatic cells compared with metformin and BC1618.