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Towards metabolically stable 5-HT7 receptor ligands: a study on 1-arylpiperazine derivatives and related isosters

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Abstract

Serotonin 7 (5-hydroxytryptamine7 or 5-HT7) is the most recently identified serotonin receptor. It is involved in mood disorders and is studied as a target for antidepressants. Here, we report on the structural manipulation of the 5-HT7 receptor ligand 4-[2-(3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)piperazine (1a) aimed at obtaining 5-HT7 receptor ligands endowed with good in vitro metabolic stability. A set of N-[3-methoxyphenyl)ethyl-substituted] 1-arylpiperazine, 4-arylpiperidine and 1-aryl-4-aminopiperidine was synthesized and tested in radioligand binding assays at human cloned 5-HT7 and 5-HT1A receptors. In vitro metabolic stability of the target compounds was assessed after incubation with rat hepatic S9 microsomal fraction. Among the new compounds, 1-(2-biphenyl)-4-[2-(3-methoxyphenyl)ethyl]piperazine (1d) and 4-(2-biphenyl)-1-[2-(3-methoxyphenyl)ethyl]piperidine (2d) showed a good compromise between affinity at 5-HT7 receptor (K i = 7.5 nM and 13 nM, respectively) and in vitro metabolic stability (26 and 65 % recovery of parent compound, respectively) but were poorly selective over 5-HT1A receptor.

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Acknowledgments

The authors gratefully acknowledge the financial support from the Italian Ministry of Health Under-40 Young Investigator Project, call 2007, “ADHD-sythe” (P.I.: W. Adriani; local unit: Enza Lacivita).

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Authors and Affiliations

  1. Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “A. Moro”, via Orabona, 4, 70125, Bari, Italy

    Enza Lacivita, Paola De Giorgio, Daniela Patarnello, Mauro Niso, Nicola A. Colabufo, Francesco Berardi, Roberto Perrone & Marcello Leopoldo

  2. Department of Medicinal Chemistry, Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343, Kraków, Poland

    Grzegorz Satala, Beata Duszynska & Andrzej J. Bojarski

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  1. Enza Lacivita
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  2. Paola De Giorgio
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  3. Daniela Patarnello
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  4. Mauro Niso
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  5. Nicola A. Colabufo
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  6. Francesco Berardi
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  8. Grzegorz Satala
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  11. Marcello Leopoldo
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Correspondence to Marcello Leopoldo.

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Lacivita, E., De Giorgio, P., Patarnello, D. et al. Towards metabolically stable 5-HT7 receptor ligands: a study on 1-arylpiperazine derivatives and related isosters. Exp Brain Res 230, 569–582 (2013). https://doi.org/10.1007/s00221-013-3498-0

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