Synthesis, Biological Evaluation and Molecular Modeling of 1-oxa-4-thiaspiro- And 1,4-dithiaspiro[4.5]decane Derivatives as Potent and Selective 5-HT 1A Receptor Agonists

Eur J Med Chem. 2017 Jan 5;125:435-452. doi: 10.1016/j.ejmech.2016.09.050. Epub 2016 Sep 17.

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.

Keywords: 5-HT1A receptor; Agonist; Analgesic activity; BBB penetration; Neuroprotection.

MeSH terms

  • Alkanes / chemistry*
  • Alkanes / pharmacokinetics
  • Alkanes / pharmacology
  • Alkanes / therapeutic use*
  • Analgesics / chemistry*
  • Analgesics / pharmacokinetics
  • Analgesics / pharmacology
  • Analgesics / therapeutic use*
  • Animals
  • Blood-Brain Barrier / metabolism
  • Formaldehyde
  • Humans
  • Male
  • Mice
  • Models, Molecular
  • Pain / chemically induced
  • Pain / drug therapy*
  • Pain Measurement
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Serotonin 5-HT1 Receptor Agonists / chemistry*
  • Serotonin 5-HT1 Receptor Agonists / pharmacokinetics
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Serotonin 5-HT1 Receptor Agonists / therapeutic use*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Structure-Activity Relationship

Substances

  • Alkanes
  • Analgesics
  • Serotonin 5-HT1 Receptor Agonists
  • Spiro Compounds
  • Receptor, Serotonin, 5-HT1A
  • Formaldehyde
  • decane