Format

Send to

Choose Destination
Eur J Med Chem. 2014 Jun 10;80:8-35. doi: 10.1016/j.ejmech.2014.04.034. Epub 2014 Apr 13.

Towards the development of 5-HT₇ ligands combining serotonin-like and arylpiperazine moieties.

Author information

1
Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino, Piazza Rinascimento 6, I-61029 Urbino, PU, Italy.
2
Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy.
3
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Italy.
4
Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy. Electronic address: silvia.rivara@unipr.it.
5
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Italy. Electronic address: patrizia.minetti@virgilio.it.

Abstract

Many known 5-HT7 ligands contain either a serotonin-like or an arylpiperazine structure that, in published SAR studies, are generally supposed to bind the same receptor pocket. Conversely, we explored the hypothesis that two such moieties can co-exist in the same ligand, binding to different pockets. We thus designed and synthesized a set of compounds including both a 5-hydroxyindol-3-ylethyl and a 1-arylpiperazine moieties connected by a short linker. The compounds were tested for their affinity for human 5-HT7 serotonin receptor. We further prepared a novel series of 5-HT7 ligands, where the 5-hydroxyindol-3-ylethyl moiety was bioisosterically replaced by a 3-hydroxyanilinoalkyl one. Among the newly synthesized compounds, potent ligands at the 5-HT7 receptor, behaving as antagonists in functional tests, were identified, even if they showed limited subtype selectivity. Docking studies within a model of the 5-HT7 receptor showed that the binding site can actually accommodate both moieties, with the serotonin-like one in the putative orthosteric site and the arylpiperazine one occupying an accessory pocket. The present results demonstrate that it is possible to devise and develop new 5-HT7 ligands merging two privileged structures in the same molecule.

KEYWORDS:

5-HT(7); Chemical synthesis; Medicinal chemistry; Molecular modeling; Serotonin; Structure–activity relationships

PMID:
24763360
DOI:
10.1016/j.ejmech.2014.04.034
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center