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Eur J Med Chem. 2017 Jan 5;125:233-244. doi: 10.1016/j.ejmech.2016.09.026. Epub 2016 Sep 9.

The replacement of the 2-methoxy substituent of N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine improves the selectivity for 5-HT1A receptor over α1-adrenoceptor and D2-like receptor subtypes.

Author information

1
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
2
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, Baltimore, MD, 333 Cassell Drive, Baltimore, MD 21224, USA.
3
Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, Baltimore, MD, 333 Cassell Drive, Baltimore, MD 21224, USA; Department of Chemistry & Biochemistry, College of Science and Mathematics, Rowan University 201 Mullica Hill Rd, Glassboro, NJ 08028, USA; Department of Biomedical & Translational Sciences, College of Science and Mathematics, Rowan University 201 Mullica Hill Rd, Glassboro, NJ 08028, USA.
4
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
5
Recordati S.p.A., Drug Discovery, Via Civitali 1, 20148 Milano, Italy.
6
Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino (NEUROFARBA), Sezione di Farmacologia e Tossicologia, Universita' degli Studi di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy.
7
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy. Electronic address: wilma.quaglia@unicam.it.

Abstract

N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine (3) is a potent 5-HT1A receptor and α1d-adrenoceptor (α1d-AR) ligand. Analogues 5-10 were rationally designed and prepared to evaluate whether electronic and/or lipophilic properties of substituents in the ortho position of its phenoxy moiety exert any favorable effects on the affinity/activity at 5-HT1A receptor and improve selectivity over α1-ARs. To rationalize the experimental observations and derive information about receptor-ligand interactions of the reported ligands, docking studies, using 5-HT1A and α1d-AR models generated by homology techniques, and a retrospective computational study were performed. The results highlighted that proper substituents in position 2 of the phenoxy moiety of 3 selectively address the ligands toward 5-HT1A receptor with respect to α1-ARs and D2-like receptor subtypes. Methoxymethylenoxy derivative 9 showed the best 5-HT1A selectivity profile and the highest potency at 5-HT1A receptor, behaving as a partial agonist. Finally, 9, tested in light/dark exploration test in mice, significantly reduced anxiety-linked behaviors. Therefore, it may be considered a lead for the design of partial agonists potentially useful in the treatment of disorders in which 5-HT1A receptor is involved.

KEYWORDS:

5-HT(1A) receptor; Anxiolytic effect; D(2)-like receptor subtypes; Docking studies; Selective 5-HT(1A) receptor agonists; α(1)-Adrenoceptor subtypes

PMID:
27662034
DOI:
10.1016/j.ejmech.2016.09.026
[Indexed for MEDLINE]

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