2. Academic Validation
  3. Novel anilide and benzylamide derivatives of arylpiperazinylalkanoic acids as 5-HT1A/5-HT7 receptor antagonists and phosphodiesterase 4/7 inhibitors with procognitive and antidepressant activity

Novel anilide and benzylamide derivatives of arylpiperazinylalkanoic acids as 5-HT1A/5-HT7 receptor antagonists and phosphodiesterase 4/7 inhibitors with procognitive and antidepressant activity

  • Eur J Med Chem. 2020 Sep 1;201:112437. doi: 10.1016/j.ejmech.2020.112437.
Agnieszka Jankowska 1,  Grzegorz Satała 2,  Marcin Kołaczkowski 1,  Adam Bucki 1,  Monika Głuch-Lutwin 3,  Artur Świerczek 4,  Krzysztof Pociecha 4,  Anna Partyka 5,  Magdalena Jastrzębska-Więsek 5,  Annamaria Lubelska 6,  Gniewomir Latacz 6,  Alicja Gawalska 1,  Andrzej J Bojarski 2,  Elżbieta Wyska 4,  Grażyna Chłoń-Rzepa 7
Affiliations

Affiliations

  • 1 Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688, Kraków, Poland.
  • 2 Polish Academy of Sciences, Maj Institute of Pharmacology, Department of Medicinal Chemistry, 12 Smętna Street, 31-343, Kraków, Poland.
  • 3 Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacobiology, 9 Medyczna Street, 30-688, Kraków, Poland.
  • 4 Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacokinetics and Physical Pharmacy, 9 Medyczna Street, 30-688, Kraków, Poland.
  • 5 Jagiellonian University Medical College, Faculty of Pharmacy, Department of Clinical Pharmacy, 9 Medyczna Street, 30-688, Kraków, Poland.
  • 6 Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688, Kraków, Poland.
  • 7 Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688, Kraków, Poland. Electronic address: grazyna.chlon-rzepa@uj.edu.pl.
PMID: 32673902 DOI: 10.1016/j.ejmech.2020.112437
Abstract

A library of novel anilide and benzylamide derivatives of ω-(4-(2-methoxyphenyl)piperazin-1-yl)alkanoic acids as combined 5-HT1A/5-HT7 receptor ligands and phosphodiesterase PDE4B/PDE7A inhibitors was designed using a structure-based drug design approach. The in vitro studies of 33 newly synthesized compounds (7-39) allowed us to identify 22 as the most promising multifunctional 5-HT1A/5-HT7 receptor antagonist (5-HT1AKi = 8 nM, Kb = 0.04 nM; 5-HT7Ki = 451 nM, Kb = 460 nM) with PDE4B/PDE7A inhibitory activity (PDE4B IC50 = 80.4 μM; PDE7A IC50 = 151.3 μM). Compound 22 exerted a very good ability to passively penetrate through biological membranes and a high metabolic stability in vitro. Moreover, the pharmacological evaluation of 22 showed its procognitive and antidepressant properties in rat behavioral tests. Compound 22 at a dose of 3 mg/kg (i.p.) significantly reversed MK-801-induced episodic memory deficits in the novel object recognition test, while at a dose of 10 mg/kg (i.p.) reduced the immobility time of Animals (by about 34%) in the forced swimming test. The antidepressant-like effect produced by compound 22 was stronger than that of escitalopram used as a reference drug. This study opens a new perspective in the search for efficacious drugs for the treatment of cognitive and depressive disorders.

Keywords

1-(2-methoxyphenyl)piperazine derivative; 5-HT(1A)/5-HT(7) receptor antagonist; Anilide; Benzylamide; PDE4/PDE7 inhibitor; Procognitive and antidepressant activity.

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