1,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity

A series of compounds generated by ring expansion/opening and molecular elongation/simplification of the 1,3-dioxolane scaffold were prepared and tested for binding affinity at 5-HT1AR and α1 adrenoceptors. The compounds with greater affinity were selected for further functional studies. N-((2,2-dip...

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Published in:European journal of medicinal chemistry 2019-08, Vol.176, p.310-325
Main Authors: Franchini, Silvia, Sorbi, Claudia, Linciano, Pasquale, Carnevale, Gianluca, Tait, Annalisa, Ronsisvalle, Simone, Buccioni, Michela, Del Bello, Fabio, Cilia, Antonio, Pirona, Lorenza, Denora, Nunzio, Iacobazzi, Rosa Maria, Brasili, Livio
Format: Article
Language:English
Subjects:
1,3-Dioxane
5-HT1A receptor agonist
Anti-depressant
Antinociceptive activity
Anxiolytic
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Summary:A series of compounds generated by ring expansion/opening and molecular elongation/simplification of the 1,3-dioxolane scaffold were prepared and tested for binding affinity at 5-HT1AR and α1 adrenoceptors. The compounds with greater affinity were selected for further functional studies. N-((2,2-diphenyl-1,3-dioxan-5-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-ammonium hydrogen oxalate (12) emerged as highly potent full agonist at the 5-HT1AR (pKi 5-HT1A = 8.8; pD2 = 9.22, %Emax = 92). The pharmacokinetic data in rats showed that the orally administered 12 has a high biodistribution in the brain compartment. Thus, 12 was further investigated in-vivo, showing an anxiolytic and antidepressant effect. Moreover, in the formalin test, 12 was able to decrease the late response to the noxious stimulus, indicating a potential use in the treatment of chronic pain. [Display omitted] •A new series of 1,3-dioxolane analogues were prepared and tested in vitro for binding affinity, potency, efficacy at 5-HT1AR and α1 adrenoceptors.•Compound 12 emerged as a potent and selective 5-HT1AR agonist with an high biodistribution in the brain compartment as assessed by pharmacokinetic data in rats.•Compound 12 exhibited anxiolytic (Elevated Plus Maze and Open Field test) and antidepressant (Forced Swim test) effect.•Compound 12 showed anti-nociceptive activity in the formalin test.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2019.05.024