2. Academic Validation
  3. Unlocking the potential of higher-molecular-weight 5-HT7R ligands: Synthesis, affinity, and ADMET examination

Unlocking the potential of higher-molecular-weight 5-HT7R ligands: Synthesis, affinity, and ADMET examination

  • Bioorg Chem. 2024 Jul 24:151:107668. doi: 10.1016/j.bioorg.2024.107668.
Patryk Pyka 1,  Sabrina Garbo 2,  Aleksandra Murzyn 3,  Grzegorz Satała 3,  Artur Janusz 4,  Michał Górka 4,  Wojciech Pietruś 5,  Filip Mituła 4,  Delfina Popiel 4,  Maciej Wieczorek 6,  Biagio Palmisano 2,  Alessia Raucci 7,  Andrzej J Bojarski 3,  Clemens Zwergel 8,  Ewa Szymańska 9,  Katarzyna Kucwaj-Brysz 9,  Cecilia Battistelli 10,  Jadwiga Handzlik 11,  Sabina Podlewska 12
Affiliations

Affiliations

  • 1 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Kraków, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, 31-530 Kraków, Poland.
  • 2 Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome.
  • 3 Maj Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland.
  • 4 Preclinical Development Department, Celon Pharma S.A., R&D Centre, Marymoncka 15, 05-152 Kazuń Nowy, Poland.
  • 5 Medicinal Chemistry Department, Celon Pharma S.A., R&D Centre, Marymoncka 15, 05-152 Kazuń Nowy, Poland.
  • 6 Preclinical Development Department, Celon Pharma S.A., R&D Centre, Marymoncka 15, 05-152 Kazuń Nowy, Poland; Clinical Development Department, Celon Pharma S.A., R&D Centre, Marymoncka 15, 05-152 Kazuń Nowy, Poland.
  • 7 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
  • 8 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123 Saarbrücken, Germany.
  • 9 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
  • 10 Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome. Electronic address: cecilia.battistelli@uniroma1.it.
  • 11 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address: j.handzlik@uj.edu.pl.
  • 12 Maj Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland. Electronic address: smusz@if-pan.krakow.pl.
PMID: 39079393 DOI: 10.1016/j.bioorg.2024.107668
Abstract

An increasing number of drugs introduced to the market and numerous repositories of compounds with confirmed activity have posed the need to revalidate the state-of-the-art rules that determine the ranges of properties the compounds should possess to become future drugs. In this study, we designed a series of two chemotypes of aryl-piperazine hydantoin ligands of 5-HT7R, an attractive target in search for innovative CNS drugs, with higher molecular weight (close to or over 500). Consequently, 14 new compounds were synthesised and screened for their receptor activity accompanied by extensive docking studies to evaluate the observed structure-activity/properties relationships. The ADMET characterisation in terms of the biological membrane permeability, metabolic stability, hepatotoxicity, cardiotoxicity, and protein plasma binding of the obtained compounds was carried out in vitro. The outcome of these studies constituted the basis for the comprehensive challenge of computational tools for ADMET properties prediction. All the compounds possessed high affinity to the 5-HT7R (Ki below 250 nM for all analysed structures) with good selectivity over 5-HT6R and varying affinity towards 5-HT2AR, 5-HT1AR and D2R. For the best compounds of this study, the expression profile of genes associated with neurodegeneration, anti-oxidant response and anti-inflammatory function was determined, and the survival of the cells (SH-SY5Y as an in vitro model of Alzheimer's disease) was evaluated. One 5-HT7R agent (32) was characterised by a very promising ADMET profile, i.e. good membrane permeability, low hepatotoxicity and cardiotoxicity, and high metabolic stability with the simultaneous high rate of plasma protein binding and high selectivity over Other GPCRs considered, together with satisfying gene expression profile modulations and neural cell survival. Such encouraging properties make it a good candidate for further testing and optimisation as a potential agent in the treatment of CNS-related disorders.

Keywords

ADMET properties; Docking; G protein-coupled receptors; Gene expression assay; MTS assay; Molecular modelling; Serotonin receptor 5-HT(7); in vitro experiments.

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