Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists

Silvia Franchini, Leda Ivanova Manasieva, Claudia Sorbi, Umberto M. Battisti, Paola Fossa, Elena Cichero, Nunzio Denora, Rosa Maria Iacobazzi, Antonio Cilia, Lorenza Pirona, Simone Ronsisvalle, Giuseppina Aricò, Livio Brasili

Research output: Contribution to journalArticle

Abstract

Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HT1AR agonist with a moderate 5-HT1AR selectivity. In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested for binding affinity and activity at 5-HT1AR and α1 adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HT1AR partial agonists, the first being outstanding for selectivity (5-HT1A1d = 80), the latter for potency (pD2 = 9.58) and efficacy (Emax = 74%). Theoretical studies of ADME properties shows a good profile for the entire series and MDCKII-MDR1 cells permeability data predict a good BBB permeability of compound 15, which possess a promising neuroprotective activity. Furthermore, in mouse formalin test, compound 15 shows a potent antinociceptive activity suggesting a new strategy for pain control.

Original languageEnglish
Pages (from-to)435-452
Number of pages18
JournalEuropean Journal of Medicinal Chemistry
Volume125
DOIs
Publication statusPublished - Jan 5 2017

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Keywords

  • 5-HT1A receptor
  • Agonist
  • Analgesic activity
  • BBB penetration
  • Neuroprotection

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Franchini, S., Manasieva, L. I., Sorbi, C., Battisti, U. M., Fossa, P., Cichero, E., Denora, N., Iacobazzi, R. M., Cilia, A., Pirona, L., Ronsisvalle, S., Aricò, G., & Brasili, L. (2017). Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists. European Journal of Medicinal Chemistry, 125, 435-452. https://doi.org/10.1016/j.ejmech.2016.09.050