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Eur J Med Chem. 2014 Nov 24;87:248-66. doi: 10.1016/j.ejmech.2014.09.070. Epub 2014 Sep 27.

Structure-affinity/activity relationships of 1,4-dioxa-spiro[4.5]decane based ligands at α<alpha>1 and 5-HT1A receptors.

Author information

1
Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41125 Modena, Italy.
2
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
3
Dipartimento di Scienze Chimiche, Università degli Studi di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
4
Divisione Ricerca e Sviluppo, Recordati S.p.A., Via Civitali 1, 20148 Milano, Italy.
5
Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41125 Modena, Italy. Electronic address: livio.brasili@unimore.it.

Abstract

Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a highly selective and potent 5-HT1AR ligand. In the present work we adopted an in-parallel synthetic strategy to rapidly explore a new set of arylpiperazine (7-32) that is structurally related to 1. The compounds were tested for binding affinity and functional activity at 5-HT1AR and α<alpha>1-adrenoceptor subtypes and SAR studies were drawn. In particular, compounds 9, 27 and 30 emerged as promising α<alpha>1 receptor antagonists, while compound 10 behaves as the most potent and efficacious 5-HT1AR agonist. All the compounds were docked into the 5HT1AR theoretical model and the results were in agreement with the biological experimental data. These findings may represent a new starting point for developing more selective α<alpha>1 or 5-HT1AR ligands.

KEYWORDS:

1,3-Dioxolane; 5-HT(1A)R; Arylpiperazine derivatives; Structure–affinity/activity relationships; α<alpha>1 receptor

PMID:
25261823
DOI:
10.1016/j.ejmech.2014.09.070
[Indexed for MEDLINE]

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