New 5-hydroxytryptamine1A receptor ligands containing a norbornene nucleus: Synthesis and in vitro pharmacological evaluation

Ferdinande Fiorino, Elisa Perissutti, Beatrice Severino, Vincenzo Santagada, Donatella Cirillo, Sara Terracciano, Paola Massarelli, Giancarlo Bruni, Elga Collavoli, Christian Renner, Giuseppe Caliendo

Research output: Contribution to journalArticlepeer-review

Abstract

New arylpiperazine derivatives were prepared to identify highly selective and potent ligands for the 5-hydroxytryptamine 1A (5-HT1A) receptor as potential pharmacological tools in studies of central nervous system (CNS) disorders. The combination of structural elements (heterocyclic nucleus, oxyalkyl chain, and arylpiperazine) known to introduce 5-HT1A receptor affinity and the proper selection of substituents led to compounds with higher receptor specificity and affinity. In binding studies, several molecules showed affinity in the nanomolar and subnanomolar ranges at 5-HT1A and moderate to no affinity for other relevant receptors (5-HT2A, 5-HT2C, D1, D2, α1, and α2). The 4-[3-[4-(o-methoxyphenyl)piperazin-1-yl]propoxy]-4- aza-tricyclo-[5.2.1.02,6]dec-8-ene-3,5-dione (3b), with Ki = 0.021 nM, was the most active and selective derivative for the 5-HT1A receptor with respect to other serotonin receptors, whereas the most selective derivative for dopaminergic and adrenergic receptors was a CF 3-substituted arylpiperazine (2e). As a general trend, compounds with a piperazinylpropoxy chain (3b-g) showed a preferential affinity for the 5-HT1A receptor, suggesting that the alkyl chain length represents a critical structural feature in determining 5-HT1A receptor affinity and selectivity, as confirmed by the molecular modeling invoked for explaining the differential binding affinities of the new arylpiperazines.

Original languageEnglish
Pages (from-to)5495-5503
Number of pages9
JournalJournal of Medicinal Chemistry
Volume48
Issue number17
DOIs
Publication statusPublished - Aug 25 2005

ASJC Scopus subject areas

  • Organic Chemistry

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