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

Abstract

Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HT_1AR agonist with a moderate 5-HT_1AR 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-HT_1AR and α₁ adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HT_1AR partial agonists, the first being outstanding for selectivity (5-HT_1A/α_1d = 80), the latter for potency (pD₂ = 9.58) and efficacy (E_max = 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.