TY - JOUR
T1 - Multitarget 1,4-Dioxane Compounds Combining Favorable D2-like and 5-HT1A 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
N1 - Funding Information:
*Phone +390737402368. E-mail gianfabio.giorgioni@unicam. it. ORCID Amy H. Newman: 0000-0001-9065-4072 Thomas M. Keck: 0000-0003-1845-9373 Gianfabio Giorgioni: 0000-0002-9576-6580 Alessandro Piergentili: 0000-0001-6135-6826 Loredana Cappellacci: 0000-0001-8155-7211 Silvia Franchini: 0000-0002-6320-9712 Wilma Quaglia: 0000-0002-7708-0200 Author Contributions #F.D.B. and D.A. contributed equally. F.D.B., D.A., M.G., G.G., A.P., L.C., S.F., and W.Q. designed the novel compounds and planned the procedures for their synthesis. F.D.B. and D.A. developed the chemical synthesis and characterized the novel compounds. They wrote the relative chemical experimental parts of the manuscript. A.C. performed binding experiments at 5-HT1A receptors and α1-AR subtypes. A.B., T.M.K., and A.H.N. performed binding experiments at dopamine D2, D3, and D4 receptors, provided functional assays through the NIDA Addiction Treatment Discovery Program contract with Oregon Health & Science University, and discussed the biological data. G.G. and W.Q. drafted the main text of the manuscript. All authors critically discussed and approved the final version of the manuscript. Funding This work was supported by grants from the University of Camerino and National Institute on Drug Abuse. Notes The authors declare no competing financial interest.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/5/15
Y1 - 2019/5/15
N2 - 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 - 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.
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U2 - 10.1021/acschemneuro.8b00677
DO - 10.1021/acschemneuro.8b00677
M3 - Article
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 -