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  3. Rational optimization of D3R/GSK-3β dual target-directed ligands as potential treatment for bipolar disorder: Design, synthesis, X-ray crystallography, molecular dynamics simulations, in vitro ADME, and in vivo pharmacokinetic studies

Rational optimization of D3R/GSK-3β dual target-directed ligands as potential treatment for bipolar disorder: Design, synthesis, X-ray crystallography, molecular dynamics simulations, in vitro ADME, and in vivo pharmacokinetic studies

  • Eur J Med Chem. 2025 Jun 25:297:117899. doi: 10.1016/j.ejmech.2025.117899.
R M C Di Martino 1,  D Russo 2,  I Penna 2,  S Demuro 3,  A Dalle Vedove 4,  R Spagnuolo 5,  G Ottonello 6,  S M Bertozzi 6,  M Summa 7,  J Desantis 8,  A Valeri 9,  L Pruccoli 10,  S K Tripathi 11,  A Tarozzi 10,  P Storici 12,  S Girotto 11,  R Bertorelli 7,  A Armirotti 6,  G Cruciani 8,  T Bandiera 2,  A Cavalli 3,  G Bottegoni 13
Affiliations

Affiliations

  • 1 Computational and Chemical Biology, Istituto Italiano di Tecnologia, via Morego 30, 16163, Genova (GE), Italy. Electronic address: rita.dimartino@uniupo.it.
  • 2 D3 PharmaChemistry, Istituto Italiano di Tecnologia, via Morego 30, 16163, Genova (GE), Italy.
  • 3 Computational and Chemical Biology, Istituto Italiano di Tecnologia, via Morego 30, 16163, Genova (GE), Italy; Department of Pharmacy and Biotechnology, University of Bologna, via Belmeloro 6, 40126, Bologna (BO), Italy.
  • 4 Area Science Park, Padriciano 99, Trieste, Italy.
  • 5 Department of Biomolecular Sciences, University of Urbino, Campus Scientifico Enrico Mattei, via Ca' Le Suore 2/4, 61029, Urbino (PU), Italy.
  • 6 Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego 30, 16163, Genova (GE), Italy.
  • 7 Translational Pharmacology Facility, Istituto Italiano di Tecnologia, via Morego 30, 16163, Genova (GE), Italy.
  • 8 Department of Chemistry, Biology and Biotechnology, University of Perugia, via dell'Elce di Sotto 8, 06123, Perugia (PG), Italy.
  • 9 Molecular Horizon srl, via Montelino 20, 06084, Bettona (PG), Italy.
  • 10 Department for Life Quality Studies, University of Bologna, Corso d'Augusto 237, 47921, Rimini (RN), Italy.
  • 11 Computational and Chemical Biology, Istituto Italiano di Tecnologia, via Morego 30, 16163, Genova (GE), Italy.
  • 12 Protein Targets for Drug Discovery Lab, Structural Biology, Elettra Sincrotrone Trieste, SS 14 Km 163.5 in AREA Science Park, Basovizza, Trieste, Italy.
  • 13 Department of Biomolecular Sciences, University of Urbino, Campus Scientifico Enrico Mattei, via Ca' Le Suore 2/4, 61029, Urbino (PU), Italy; School of Pharmacy, University of Birmingham, Edgbaston, B15 2TT, Birmingham, UK. Electronic address: giovanni.bottegoni@uniurb.it.
PMID: 40639291 DOI: 10.1016/j.ejmech.2025.117899
Abstract

Bipolar disorder is a complex neuropsychiatric condition with a significant unmet medical need, as current treatments lack disease-modifying properties and multimodal therapeutic effects. To overcome the limitations of single-target drugs, we designed dual-target ligands that combine partial agonism at the dopamine D3 receptor (D3R) with inhibition of glycogen synthase kinase-3β (GSK-3β). We previously identified ARN24161 (1) as a promising prototype, demonstrating partial agonism at D3R (EC50 = 10.1 nM, % Eff. = 26.3) and GSK-3β inhibition (IC50 = 561 nM). However, its drug-like properties remained suboptimal. To optimize this compound, we initiated a multidisciplinary refinement campaign, leveraging computational modeling and crystallographic data to fine-tune the balance between D3R and GSK-3β activity, reduce P-glycoprotein (P-gp) affinity, and improve the pharmacokinetic profile. This effort led to the identification of ARN25297 (5), a moderately balanced dual-target ligand that exhibits partial agonism at D3R (EC50 = 13.1 nM, % Eff. = 17.1) and potent GSK-3β inhibition (IC50 = 47.0 nM). Notably, ARN25657 (16) emerged as the most well-balanced candidate, demonstrating enhanced D3R partial agonism (EC50 = 15.2 nM, % Eff. = 37.7) alongside strong GSK-3β inhibition (IC50 = 19.3 nM). Compound 16 also exhibited the lowest P-gp inhibition and significant improvements in in vitro ADME properties compared to prototype 1, while maintaining a balanced dual target profile. Although the PK profile of 16 remained comparable to that of prototype 1, these findings lay the groundwork for further lead optimization and structural refinement, driving future in vivo proof-of-concept toward innovative therapeutic strategies for bipolar disorder and related neuropsychiatric conditions.

Keywords

Bipolar disorder; Dopamine D3 receptor (D3R); Dual target-directed ligands; Glycogen synthase kinase-3β (GSK-3β); Molecular dynamics; Multi-target compounds.

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