1. 1,3-Dioxane as a scaffold for potent and selective 5-HT 1A R agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity.
- Author
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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, and Brasili L
- Subjects
- Analgesics chemical synthesis, Analgesics pharmacokinetics, Analgesics toxicity, Animals, Anti-Anxiety Agents chemical synthesis, Anti-Anxiety Agents pharmacokinetics, Anti-Anxiety Agents toxicity, Antidepressive Agents chemical synthesis, Antidepressive Agents pharmacokinetics, Antidepressive Agents toxicity, Brain metabolism, Dioxanes chemical synthesis, Dioxanes pharmacokinetics, Dioxanes toxicity, Male, Neuroprotective Agents chemical synthesis, Neuroprotective Agents pharmacokinetics, 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 toxicity, Stereoisomerism, Structure-Activity Relationship, Analgesics therapeutic use, Anti-Anxiety Agents therapeutic use, Antidepressive Agents therapeutic use, Dioxanes therapeutic use, Neuroprotective Agents therapeutic use, Serotonin 5-HT1 Receptor Agonists therapeutic use
- 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
1A R 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-HT1A R (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., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)- Published
- 2019
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