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-HTR agonist with a moderate 5-HTR 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-HTR and α adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HTR partial agonists, the first being outstanding for selectivity (5-HT/α = 80), the latter for potency (pD = 9.58) and efficacy (E = 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.

4WD to Travel Inside the 5-HT1A Receptor World

“…The isosteric replacement of one (oxathiolane derivative 36) and especially of two (dithiolane derivative 37) oxygen atoms with sulfur atoms proves to be tolerated (Figure 21). The replacement of the piperazine ring with a more flexible basic chain affords compound 38, which behaves as a potent and selective 5-HT 1A R partial agonist endowed with neuroprotective activity in vitro and potent antinociceptive activity in an in vivo model [28]. A similar profile is shown by the unsubstituted analogue 39 characterized by good 5-HT 1A / α 1 -AR selectivity (Figure 21).…”

“…Compound 35, for example, is a potent partial agonist and shows moderate selectivity over α 1 -ARs (Figure 21) [28]. Substitutions at C-8 position of the 1,4-dioxaspiro [4,5]decane moiety reduce 5-HT 1A R/α 1 -AR selectivity ratio because of the significant decrease of binding affinity and intrinsic activity for 5-HT 1A Rs with respect to α 1 -ARs.…”

Structure–Activity Relationships within a Series of σ1 and σ2 Receptor Ligands: Identification of a σ2 Receptor Agonist (BS148) with Selective Toxicity against Metastatic Melanoma

“…All compounds were evaluated for their binding affinity at σ 1 , σ 2, 5HT 1A , and α 1 adrenoceptors (Tables and ). The 5‐HT 1A and α 1 adrenoceptors were investigated, as most of the molecules share chemical features with previously published 5‐HT 1A R and α 1 ligands . None of the compounds were found to bind to the α 1 adrenoceptors; therefore, these data were not included in the Tables.…”

“…The rational design of novel σ 1 R ligands was efficiently driven by deepening computational methods, including homology modeling of the biological target, as well as pharmacophore‐based criteria. Indeed, several series of derivatives fulfilling specific patterns of chemical features have been described in the literature .…”

“…General procedure A : The selected halogen derivatives 2 – 5 and 13 and 14 (1.0 mmol) were added portionwise to a solution of 4‐benzylpiperidine or 1‐benzylpiperazine (3.0 mmol) and KI (0.2 mmol) in anhydrous 2‐methoxyethanol (10 mL). The resulting mixture was heated at reflux for 12 h or using microwave irradiation (160 °C for 30 min), then cooled to room temperature and concentrated in vacuo.…”