2. Academic Validation
  3. New N-aryl-N'-aryl-/(thio)ureido-/sulfamoylamino-derivatives of alkyl/alkylcarbamoyl piperazines: Effect of structural modifications on selectivity over 5-HT1A receptor

New N-aryl-N'-aryl-/(thio)ureido-/sulfamoylamino-derivatives of alkyl/alkylcarbamoyl piperazines: Effect of structural modifications on selectivity over 5-HT1A receptor

  • Eur J Med Chem. 2022 May 5;235:114319. doi: 10.1016/j.ejmech.2022.114319.
Przemysław Zaręba 1,  Paweł Śliwa 2,  Grzegorz Satała 3,  Paweł Zajdel 4,  Gniewomir Latacz 5,  Jolanta Jaśkowska 2
Affiliations

Affiliations

  • 1 Faculty of Chemical Engineering and Technology, Department of Chemical Technology and Environmental Analytics, Cracow University of Technology, 24 Warszawska Street, 31-155, Cracow, Poland. Electronic address: [email protected].
  • 2 Faculty of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, Cracow University of Technology, 24 Warszawska Street, 31-155, Cracow, Poland.
  • 3 Department of Medicinal Chemistry, Maj Institute of Pharmacology - Polish Academy of Sciences, 12 Smętna Street, 31-343, Kraków, Poland.
  • 4 Department of Organic Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Kraków, Poland.
  • 5 Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Cracow, Poland.
PMID: 35367707 DOI: 10.1016/j.ejmech.2022.114319
Abstract

The 5-HT1A receptors are an important biological target in the treatment of CNS diseases. Recently, their importance in the context of non-CNS disease entities has also been postulated. In the LIGHT of these reports, we designed a new group of urea derivatives of N-aryl-N'-aryl-/(thio)ureido-/sulfamoylamino-derivatives of alkyl/alkylcarbamoyl piperazines as 5-HT1AR ligands, focusing on increasing receptor selectivity. We made structural modifications in three areas of the molecule. In the course of our research, we obtained a ligand with reduced basicity (6f), which, despite the loss of the protonable nitrogen atom, did not lose its affinity for the 5-HT1AR (Ki = 35 nM) with a simultaneous increase in selectivity. In particular, a decrease in affinity for D2R (Ki = 1940 nM) was observed, which was analyzed using molecular modeling methods, including FMO and molecular dynamics. Basic ADME-Tox parameters were characterized for 6f, confirming its potential applicability in pharmacotherapy.

Keywords

5- HT1A; ADME; Dopamine; FMO; Microwave; Molecular dynamics; Non-basic; Selectivity; Serotonin; Synthesis; Urea.

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