TY - JOUR
T1 - Multitarget 1,4-Dioxane Compounds Combining Favorable D 2 -like and 5-HT 1A Receptor Interactions with Potential for the Treatment of Parkinson's Disease or Schizophrenia
AU - Del Bello, Fabio
AU - Ambrosini, Dario
AU - Bonifazi, Alessandro
AU - Newman, Amy H.
AU - Keck, Thomas M.
AU - Giannella, Mario
AU - Giorgioni, Gianfabio
AU - Piergentili, Alessandro
AU - Cappellacci, Loredana
AU - Cilia, Antonio
AU - Franchini, Silvia
AU - Quaglia, Wilma
PY - 2019/5/15
Y1 - 2019/5/15
N2 - © 2019 American Chemical Society. The effect of methoxy and hydroxy substitutions in different positions of the phenoxy moiety of the N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-phenoxyethan-1-amine scaffold on the affinity/activity for D2-like, 5-HT1A, and α1-adrenoceptor subtypes was evaluated. Multitarget compounds with suitable combinations of dopaminergic and serotoninergic profiles were discovered. In particular, the 2-methoxy derivative 3 showed a multitarget combination of 5-HT1A/D4 agonism and D2/D3/5-HT2A antagonism, which may be a favorable profile for the treatment of schizophrenia. Interestingly, the 3-hydroxy derivative 8 behaved as a partial agonist at D2 and as a potent full agonist at D3 and D4 subtypes. In addition to its potent 5-HT1A receptor agonism, such a dopaminergic profile makes 8 a potential multitarget compound for the treatment of Parkinson's disease (PD). Indeed, the activation of 5-HT1A receptors might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation.
AB - © 2019 American Chemical Society. The effect of methoxy and hydroxy substitutions in different positions of the phenoxy moiety of the N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-phenoxyethan-1-amine scaffold on the affinity/activity for D2-like, 5-HT1A, and α1-adrenoceptor subtypes was evaluated. Multitarget compounds with suitable combinations of dopaminergic and serotoninergic profiles were discovered. In particular, the 2-methoxy derivative 3 showed a multitarget combination of 5-HT1A/D4 agonism and D2/D3/5-HT2A antagonism, which may be a favorable profile for the treatment of schizophrenia. Interestingly, the 3-hydroxy derivative 8 behaved as a partial agonist at D2 and as a potent full agonist at D3 and D4 subtypes. In addition to its potent 5-HT1A receptor agonism, such a dopaminergic profile makes 8 a potential multitarget compound for the treatment of Parkinson's disease (PD). Indeed, the activation of 5-HT1A receptors might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation.
UR - http://www.scopus.com/inward/record.url?scp=85060051448&partnerID=8YFLogxK
UR - http://www.mendeley.com/research/multitarget-14dioxane-compounds-combining-favorable-d-2-like-5ht-1a-receptor-interactions-potential
U2 - 10.1021/acschemneuro.8b00677
DO - 10.1021/acschemneuro.8b00677
M3 - Journal articles
C2 - 30609891
AN - SCOPUS:85060051448
VL - 10
SP - 2222
EP - 2228
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 5
ER -