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Eur J Med Chem. 2017 Jan 5;125:435-452. doi: 10.1016/j.ejmech.2016.09.050. Epub 2016 Sep 17.

Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists.

Author information

1
Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 103, 41125, Modena, Italy.
2
Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, 16132, Genova, Italy.
3
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, I-70125, Bari, Italy.
4
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, I-70125, Bari, Italy; Istituto tumori IRCCS "Giovanni Paolo II", Via Orazio Flacco, 65, 70124, Bari, Italy.
5
Divisione Ricerca e Sviluppo, Recordati S.p.A., Via Civitali 1, 20148, Milano, Italy.
6
Dipartimento di Scienze del Farmaco Sezione di Chimica Farmaceutica e sezione di Farmacologia e Tossicologia, Università degli Studi di Catania, Viale Andrea Doria 6, 95125, Catania, Italy.
7
Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 103, 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 potent 5-HT1AR agonist with a moderate 5-HT1AR selectivity. In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested for binding affinity and activity at 5-HT1AR and α1 adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HT1AR partial agonists, the first being outstanding for selectivity (5-HT1A1d = 80), the latter for potency (pD2 = 9.58) and efficacy (Emax = 74%). Theoretical studies of ADME properties shows a good profile for the entire series and MDCKII-MDR1 cells permeability data predict a good BBB permeability of compound 15, which possess a promising neuroprotective activity. Furthermore, in mouse formalin test, compound 15 shows a potent antinociceptive activity suggesting a new strategy for pain control.

KEYWORDS:

5-HT1A receptor; Agonist; Analgesic activity; BBB penetration; Neuroprotection

PMID:
27689727
DOI:
10.1016/j.ejmech.2016.09.050
[Indexed for MEDLINE]

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