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-HT1Areceptor over α1-adrenoceptor and D2-like receptor subtypes.
N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine (3) is a potent 5-HT1Areceptor 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-HT1Areceptor 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-HT1Aand 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-HT1Areceptor with respect to α1-ARs and D2-like receptor subtypes. Methoxymethylenoxy derivative 9 showed the best 5-HT1Aselectivity profile and the highest potency at 5-HT1Areceptor, 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-HT1Areceptor is involved.
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
Fabio
F
Del Bello
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.
Alessandro
A
Bonifazi
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
Mario
M
Giannella
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
Gianfabio
G
Giorgioni
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
Alessandro
A
Piergentili
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
Riccardo
R
Petrelli
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
Carlo
C
Cifani
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
Maria Vittoria
MV
Micioni Di Bonaventura
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.
Thomas M
TM
Keck
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
Angelica
A
Mazzolari
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
Giulio
G
Vistoli
Recordati S.p.A., Drug Discovery, Via Civitali 1, 20148 Milano, Italy.
Antonio
A
Cilia
Recordati S.p.A., Drug Discovery, Via Civitali 1, 20148 Milano, Italy.
Elena
E
Poggesi
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.
Rosanna
R
Matucci
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.
Wilma
W
Quaglia
D000588:Amines / Q000378:metabolism*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy; D004146:Dioxanes / Q000378:metabolism*; D005021:Ethylamines / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism*; D012189:Retrospective Studies; D013329:Structure-Activity Relationship
D000588:Amines; D014151:Anti-Anxiety Agents; D004146:Dioxanes; D005021:Ethylamines; D008024:Ligands; C000614439:N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-(methoxymethoxy)phenoxy)ethanamine; C000614438:N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine; D018340:Receptors, Adrenergic, alpha-1; D044282:Receptor, Serotonin, 5-HT1A
5-HT(1A) receptor; Anxiolytic effect; D(2)-like receptor subtypes; Docking studies; Selective 5-HT(1A) receptor agonists; α(1)-Adrenoceptor subtypes