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 -