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

• Published in: European journal of medicinal chemistry Vol. 125; p. 435
• 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: France 05-01-2017
• Subjects: 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; Neuroprotection; Agonist; BBB penetration; 5-HT1A receptor; Analgesic activity
• ISSN: 1768-3254

Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HT
R agonist with a moderate 5-HT
R 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
R and α
adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HT
R 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.