Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2 H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties

  • J Med Chem. 2025 Feb 13;68(3):2551-2573. doi: 10.1021/acs.jmedchem.4c01644.
Andrea Bagán  1  2 ,  Alba López-Ruiz  1  2 ,  Sònia Abás  1 ,  M Carmen Ruiz-Cantero  1 ,  Foteini Vasilopoulou  3 ,  Teresa Taboada-Jara  3 ,  Christian Griñán-Ferré  3  4 ,  Mercè Pallàs  3  4 ,  Carolina Muguruza  5  6 ,  Rebeca Diez-Alarcia  5  6  7 ,  Luis F Callado  5  6  7 ,  José M Entrena  8 ,  Enrique J Cobos  9 ,  Belén Pérez  10 ,  José A Morales-García  11 ,  Elies Molins  12 ,  Steven De Jonghe  13 ,  Dirk Daelemans  14 ,  José Brea  15 ,  Cristina Val  15 ,  M Isabel Loza  15 ,  Elena Hernández-Hernández  16 ,  Jesús A García-Sevilla  16 ,  M Julia García-Fuster  16 ,  Caridad Díaz  17 ,  Rosario Fernández-Godino  17 ,  Olga Genilloud  17 ,  Milan Beljkaš  18 ,  Slavica Oljačić  18 ,  Katarina Nikolic  18 ,  Carmen Escolano  1  2
Affiliations
  • 1. Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, Barcelona 08028, Spain.
  • 2. Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona 08028, Spain.
  • 3. Pharmacology Section, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institut de Neurociències, University of Barcelona, Av. Joan XXIII, 27-31, Barcelona 08028, Spain.
  • 4. Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CiberNed), National Institute of Health Carlos III, Madrid 28029, Spain.
  • 5. Department of Pharmacology, University of the Basque Country, UPV/EHU48940 Leioa, Bizkaia.
  • 6. Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain.
  • 7. BioBizkaia Health Research Institute, Barakaldo, Bizkaia 48903,Spain.
  • 8. Animal Behavior Research Unit, Scientific Instrumentation Center, Parque Tecnológico de la Salud, University of Granada, Armilla, Granada 18100, Spain.
  • 9. Department of Pharmacology, Faculty of Medicine and Biomedical Research Center (Neurosciences Institute), Biosanitary Research Institute ibs.GRANADA, University of Granada, Granada 18016, Spain.
  • 10. Department of Pharmacology, Therapeutic and Toxicology. Autonomous, University of Barcelona, Cerdanyola 08193, Spain.
  • 11. Department of Cell Biology. Faculty of Medicine, Computense University of Madrid. (UCM), Madrid 28040, Spain.
  • 12. Institut de Ciencia de Materials de Barcelona (CSIC), Campus UAB, Cerdanyola 08193, Spain.
  • 13. Molecular, Structural and Translational Virology Research Group, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven 3000, Belgium.
  • 14. Molecular Genetics and Therapeutics in Virology and Oncology Research Group, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven 3000, Belgium.
  • 15. Drug Screening Platform/Biofarma Research Group, CIMUS Research Center, University of Santiago de Compostela (USC), Santiago de Compostela 15782, Spain.
  • 16. IUNICS, University of the Balearic Islands (UIB) and IdISBa, Cra. Valldemossa km 7.5, Palma de Mallorca 07122, Spain.
  • 17. Fundación MEDINA Centro de Excelencia en Investigación de Medicamentos Innovadores de Andalucía, Avda. Del Conocimiento 34, Ganada 10016, Spain.
  • 18. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade 11000, Serbia.
PMID: 39818939 DOI: 10.1021/acs.jmedchem.4c01644
Abstract

Imidazoline I2 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.

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