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

Silvia Franchini; Claudia Sorbi; Pasquale Linciano; Gianluca Carnevale; Annalisa Tait; Simone Ronsisvalle; Michela Buccioni; Fabio Del Bello; Antonio Cilia; Lorenza Pirona; Nunzio Denora; Rosa Maria Iacobazzi; Livio Brasili

doi:10.1016/j.ejmech.2019.05.024

1,3-Dioxane as a scaffold for potent and selective 5-HT_1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity

Silvia Franchini, Claudia Sorbi, Pasquale Linciano, Gianluca Carnevale, Annalisa Tait, Simone Ronsisvalle, Michela Buccioni, Fabio Del Bello, Antonio Cilia, Lorenza Pirona, Nunzio Denora, Rosa Maria Iacobazzi, Livio Brasili

IRCCS Giovanni Paolo II

Research output: Contribution to journal › Article › peer-review

Abstract

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-HT_1AR 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-HT_1AR (pKi 5-HT_1A = 8.8; pD₂ = 9.22, %E_max = 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.

Original language	English
Pages (from-to)	310-325
Number of pages	16
Journal	European Journal of Medicinal Chemistry
Volume	176
DOIs	https://doi.org/10.1016/j.ejmech.2019.05.024
Publication status	Published - Aug 15 2019

Keywords

1,3-Dioxane
5-HT1A receptor agonist
Anti-depressant
Antinociceptive activity
Anxiolytic

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2019.05.024

Cite this

Franchini, S., Sorbi, C., Linciano, P., Carnevale, G., Tait, A., Ronsisvalle, S., Buccioni, M., Del Bello, F., Cilia, A., Pirona, L., Denora, N., Iacobazzi, R. M., & Brasili, L. (2019). 1,3-Dioxane as a scaffold for potent and selective 5-HT_1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity. European Journal of Medicinal Chemistry, 176, 310-325. https://doi.org/10.1016/j.ejmech.2019.05.024

Franchini, S, Sorbi, C, Linciano, P, Carnevale, G, Tait, A, Ronsisvalle, S, Buccioni, M, Del Bello, F, Cilia, A, Pirona, L, Denora, N, Iacobazzi, RM & Brasili, L 2019, '1,3-Dioxane as a scaffold for potent and selective 5-HT_1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity', European Journal of Medicinal Chemistry, vol. 176, pp. 310-325. https://doi.org/10.1016/j.ejmech.2019.05.024

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abstract = "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.",

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AU - Franchini, Silvia

AU - Sorbi, Claudia

AU - Linciano, Pasquale

AU - Carnevale, Gianluca

AU - Tait, Annalisa

AU - Ronsisvalle, Simone

AU - Buccioni, Michela

AU - Del Bello, Fabio

AU - Cilia, Antonio

AU - Pirona, Lorenza

AU - Denora, Nunzio

AU - Iacobazzi, Rosa Maria

AU - Brasili, Livio

PY - 2019/8/15

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N2 - 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.

AB - 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.

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