Design and synthesis of new potent 5-HT7 receptor ligands as a candidate for the treatment of central nervous system diseases

Damian Kułaga; Anna K Drabczyk; Grzegorz Satała; Gniewomir Latacz; Karolina Rózga; Damian Plażuk; Jolanta Jaśkowska

doi:10.1016/j.ejmech.2021.113931

Design and synthesis of new potent 5-HT₇ receptor ligands as a candidate for the treatment of central nervous system diseases

Eur J Med Chem. 2022 Jan 5:227:113931. doi: 10.1016/j.ejmech.2021.113931. Epub 2021 Oct 21.

Authors

Damian Kułaga¹, Anna K Drabczyk², Grzegorz Satała³, Gniewomir Latacz⁴, Karolina Rózga⁵, Damian Plażuk⁵, Jolanta Jaśkowska²

Affiliations

¹ Faculty of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, Cracow University of Technology, ul. Warszawska 24, 31-155, Kraków, Poland. Electronic address: damian.kulaga@pk.edu.pl.
² Faculty of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, Cracow University of Technology, ul. Warszawska 24, 31-155, Kraków, Poland.
³ Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, ul. Smętna 12, 31-343, Kraków, Poland.
⁴ Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, ul. Medyczna 9, 30-688, Kraków, Poland.
⁵ Department of Organic Chemistry, Faculty of Chemistry University of Łódź, ul. Tamka 12, 91-403, Łódź, Poland.

PMID: 34710746
DOI: 10.1016/j.ejmech.2021.113931

Abstract

Owing to their multifunctional pharmacological profiles (including dual 5-HT_1A/5-HT₇ action), arylpiperazine derivatives are widely used for treating central nervous system diseases including the depression or neuropathic pain. Herein we describe the design, synthesis and evaluation of biological activity of novel 5-HT₇ ligands derived of 2,4,6-triamino-1,3,5-triazine. The studied compounds showed affinity and high selectively towards 5-HT₇ receptor with the two most active compounds 34 (K_i = 61 nM), 22 (K_i = 109 nM) showing good metabolic stability and moderate affinity to CYP3A4 isoenzyme. Compound 22 had high hepatotoxicity at a concentration below 50 μM, while compound 34 showed low hepatotoxicity even at a concentration above 50 μM.

Keywords: 5-HT7; Aminotriazine; Medicinal chemistry; Microvave synthesis; lcap.

MeSH terms

Cell Proliferation / drug effects
Cell Survival / drug effects
Central Nervous System Diseases / drug therapy*
Central Nervous System Diseases / metabolism
Dose-Response Relationship, Drug
Drug Design*
Hep G2 Cells
Humans
Ligands
Models, Molecular
Molecular Structure
Receptors, Serotonin / metabolism*
Structure-Activity Relationship
Triazines / chemical synthesis
Triazines / chemistry
Triazines / pharmacology*

Substances

Ligands
Receptors, Serotonin
Triazines
serotonin 7 receptor
melamine