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

Access to Document

10.1016/j.ejmech.2019.05.024

Fingerprint Dive into the research topics of '1,3-Dioxane as a scaffold for potent and selective 5-HT<sub>1A</sub>R agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity'. Together they form a unique fingerprint.

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

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

In: European Journal of Medicinal Chemistry, Vol. 176, 15.08.2019, p. 310-325.

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

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

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. / 1,3-Dioxane as a scaffold for potent and selective 5-HT_1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 176. pp. 310-325.

@article{212efe0012464034afeeb0ac457fae32,

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

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.",

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

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

year = "2019",

month = aug,

day = "15",

doi = "10.1016/j.ejmech.2019.05.024",

language = "English",

volume = "176",

pages = "310--325",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - 1,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity

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

Y1 - 2019/8/15

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.

KW - 1,3-Dioxane

KW - 5-HT1A receptor agonist

KW - Anti-depressant

KW - Antinociceptive activity

KW - Anxiolytic

UR - http://www.scopus.com/inward/record.url?scp=85065701574&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065701574&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2019.05.024

DO - 10.1016/j.ejmech.2019.05.024

M3 - Article

C2 - 31112892

AN - SCOPUS:85065701574

VL - 176

SP - 310

EP - 325

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -