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.

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 α ₁ 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 _1A R (pKi 5-HT _1A  = 8.8; pD ₂  = 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.
(Copyright © 2019 Elsevier Masson SAS. All rights reserved.)