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

• Published in: European journal of medicinal chemistry Vol. 125; pp. 435 - 452
• Main Authors: Franchini, Silvia, Manasieva, Leda Ivanova, Sorbi, Claudia, Battisti, Umberto M., Fossa, Paola, Cichero, Elena, Denora, Nunzio, Iacobazzi, Rosa Maria, Cilia, Antonio, Pirona, Lorenza, Ronsisvalle, Simone, Aricò, Giuseppina, Brasili, Livio
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 05-01-2017
• Subjects: 5-HT1A receptor; Agonist; Analgesic activity; BBB penetration; Neuroprotection; Neuroprotection; Agonist; 5-HT1A receptor; Analgesic activity; BBB penetration
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.09.050

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-HT1A/α1d = 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.
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•1,4-dioxaspiro[4,5]dec-2-ylmethyl-amines were synthesized and tested.•Oxygen/Sulphur substitution favors 5-HT1AR affinity, potency and efficacy.•14 and 15 behave as selective and potent 5-HT1AR partial agonists.•15 shows a promising neuroprotective activity in-vitro.•15 reduces significantly the linking time in Phase II at a dose of 10 mg/kg i.p.