Synthesis and biological evaluation of 1, 3-dioxolane-based 5-HT1A receptor agonists for CNS disorders and neuropathic pain. (25th July 2018)

• Record Type: Journal Article
• Authors: Franchini, Silvia; Bencheva, Leda Ivanova; Battisti, Umberto Maria; Tait, Annalisa; Sorbi, Claudia; Fossa, Paola; Cichero, Elena; Ronsisvalle, Simone; Aricò, Giuseppina; Denora, Nunzio; Iacobazzi, Rosa Maria; Cilia, Antonio; Pirona, Lorenza; Brasili, Livio
• Is Part Of: Future medicinal chemistry. Volume 10:Number 18(2018)
• Page Start: 2137
• Page End: 2154
• Publication Date: 2018-07-25
• Subjects: 5-HT1A receptor agonist -- α1-adrenoceptors -- antinociceptive activity -- neuroprotection; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc-2018-0107
• Languages: English
• ISSNs: 1756-8919

Abstract

Aim: Targeting 5-HT1A receptor (5-HT1A R) as a strategy for CNS disorders and pain control.Methodology: A series of 1, 3-dioxolane-based 2-heteroaryl-phenoxyethylamines was synthesized by a convergent approach and evaluated at α1 -adrenoceptors and 5-HT1A R by binding and functional experiments. Absorption, distribution, metabolism, excretion and toxicity prediction studies were performed to explore the drug-likeness of the compounds.Results & conclusion: The most promising compound, the pyridin-4-yl derivative, emerged as a potent and selective 5-HT1A R agonist (pKi = 9.2; pD2 = 8.83; 5-HT1A /α1 = 135). In vitro it was able to permeate by passive diffusion MDCKII-MDR1 monolayer mimicking the blood–brain barrier and showed promising neuroprotective activity.