Synthesis, biological evaluation and molecular modelling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists

Serotonin (5-hydroxytryptamine, 5-HT) is a relevant neurotransmitter both in the central nervous system and in periphery. It mediates several physio-pathological effects through at least 14 receptor subtypes. Among them, the 5-HT1AR subtype has been extensively studied and still represents an attractive target for novel therapeutic uses. Agonists and partial agonists have been initially proven to be effective in anxiety, depression, and psychosis. More recently, they have shown pronounced neuroprotective properties indicating their potential benefit in the treatment of many neurodegenerative disorders, including Parkinson’s disease and cerebral ischemia. Currently, it has been shown that 5-HT1AR is involved at multiple levels in the regulation of nociception and 5-HT1AR agonists may represent a new approach in pain relief therapy. Moreover it was found that 5-HT1AR is implicated in oncogenesis and 5-HT1AR antagonists demonstrated their efficacy in inhibiting the growth of different tumor (prostate, small cell lung). Thus, it is of paramount importance the discovery of more potent and selective 5-HT1AR ligands. Recently, our research group reported 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) as a potent 5-HT1AR partial agonist (pD2= 8.61). 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. The results led to the identification of 15, a novel 5-HT1AR partial agonist with a 10-fold improved potency (pD2= 9.58) and about 50 % of enhanced efficacy (Emax= 74%,). MDCKII-MDR1 cells permeability assay predicted the BBB permeability of 15 that also showed a promising neuroprotective activity in vitro