Towards the development of 5-HT₇ ligands combining serotonin-like and arylpiperazine moieties.
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.
Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino, Piazza Rinascimento 6, I-61029 Urbino, PU, Italy.
Gilberto
G
Spadoni
Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino, Piazza Rinascimento 6, I-61029 Urbino, PU, Italy.
Annalida
A
Bedini
Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino, Piazza Rinascimento 6, I-61029 Urbino, PU, Italy.
Silvia
S
Bartolucci
Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy.
Daniele
D
Pala
Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy.
Marco
M
Mor
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Italy.
Teresa
T
Riccioni
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Italy.
Franco
F
Borsini
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Italy.
Walter
W
Cabri
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Italy.
Diana
D
Celona
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Italy.
Mauro
M
Marzi
Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino, Piazza Rinascimento 6, I-61029 Urbino, PU, Italy.
Giorgio
G
Tarzia
Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy. Electronic address: silvia.rivara@unipr.it.
Silvia
S
Rivara
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Italy. Electronic address: patrizia.minetti@virgilio.it.
Patrizia
P
Minetti
D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000737:chemistry*; D011487:Protein Conformation; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D012701:Serotonin / Q000737:chemistry*; D013329:Structure-Activity Relationship
D008024:Ligands; D010879:Piperazines; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D012701:Serotonin
5-HT(7); Chemical synthesis; Medicinal chemistry; Molecular modeling; Serotonin; Structure–activity relationships