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.
1,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity / 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.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 176(2019), pp. 310-325.
Data di pubblicazione: | 2019 |
Data di prima pubblicazione: | 11-mag-2019 |
Titolo: | 1,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity |
Autore/i: | 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. |
Autore/i UNIMORE: | |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1016/j.ejmech.2019.05.024 |
Rivista: | |
Volume: | 176 |
Pagina iniziale: | 310 |
Pagina finale: | 325 |
Codice identificativo ISI: | WOS:000472686100023 |
Codice identificativo Scopus: | 2-s2.0-85065701574 |
Codice identificativo Pubmed: | 31112892 |
Citazione: | 1,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity / 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.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 176(2019), pp. 310-325. |
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