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

Eur J Med Chem. 2019 Aug 15:176:310-325. doi: 10.1016/j.ejmech.2019.05.024. Epub 2019 May 11.

Authors

Affiliations

¹ Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 103, 41125, Modena, Italy.
² Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche con Interesse Trapiantologico, Oncologico e di Medicina Rigenerativa, Università degli Studi di Modena e Reggio Emilia, Via del Pozzo 71, 41125, Modena, Italy.
³ Dipartimento di Scienze del Farmaco Sezione di Chimica Farmaceutica e Sezione di Farmacologia e Tossicologia, Università degli Studi di Catania, Viale Andrea Doria 6, 95125, Catania, Italy.
⁴ Scuola in Scienze del Farmaco e dei Prodotti della Salute, Università degli Studi di Camerino, Via S. Agostino 1, 62032, Camerino, MC, Italy.
⁵ Divisione Ricerca e Sviluppo, Recordati S.p.A., Via Civitali 1, 20148, Milano, Italy.
⁶ Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, I-701C25, Bari, Italy.
⁷ IRCCS Istituto tumori "Giovanni Paolo II" of Bari, Italy, Via O. Flacco 65, 70124, Bari, Italy.
⁸ Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 103, 41125, Modena, Italy. Electronic address: livio.brasili@unimore.it.

PMID: 31112892
DOI: 10.1016/j.ejmech.2019.05.024

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.

Keywords: 1,3-Dioxane; 5-HT1A receptor agonist; Anti-depressant; Antinociceptive activity; Anxiolytic.

MeSH terms

Analgesics / chemical synthesis
Analgesics / pharmacokinetics
Analgesics / therapeutic use*
Analgesics / toxicity
Animals
Anti-Anxiety Agents / chemical synthesis
Anti-Anxiety Agents / pharmacokinetics
Anti-Anxiety Agents / therapeutic use*
Anti-Anxiety Agents / toxicity
Antidepressive Agents / chemical synthesis
Antidepressive Agents / pharmacokinetics
Antidepressive Agents / therapeutic use*
Antidepressive Agents / toxicity
Brain / metabolism
Dioxanes / chemical synthesis
Dioxanes / pharmacokinetics
Dioxanes / therapeutic use*
Dioxanes / toxicity
Male
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / pharmacokinetics
Neuroprotective Agents / therapeutic use*
Neuroprotective Agents / toxicity
Rats, Sprague-Dawley
Receptor, Serotonin, 5-HT1A / metabolism
Receptors, Adrenergic, alpha-1 / metabolism
Serotonin 5-HT1 Receptor Agonists / chemical synthesis
Serotonin 5-HT1 Receptor Agonists / pharmacokinetics
Serotonin 5-HT1 Receptor Agonists / therapeutic use*
Serotonin 5-HT1 Receptor Agonists / toxicity
Stereoisomerism
Structure-Activity Relationship

Substances

Analgesics
Anti-Anxiety Agents
Antidepressive Agents
Dioxanes
Neuroprotective Agents
Receptors, Adrenergic, alpha-1
Serotonin 5-HT1 Receptor Agonists
Receptor, Serotonin, 5-HT1A