Pyrroloquinoxaline derivatives as high-affinity and selective 5-HT3 receptor agonists: Synthesis, further structure-activity relationships, and biological studies

Giuseppe Campiani, Elena Morelli, Sandra Gemma, Vito Nacci, Stefania Butini, Michel Hamon, Ettore Novellino, Giovanni Greco, Alfredo Cagnotto, Mara Goegan, Luigi Cervo, Fabio Dalla Valle, Claudia Fracasso, Silvio Caccia, Tiziana Mennini

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Abstract

The synthesis, pharmacological evaluation, and structure-activity relationships (SARs) of a series of novel pyrroloquinoxalines and heteroaromatic-related derivatives are described. The new pyrroloquinoxaline- related ligands were tested in rat cortex, a tissue expressing high density of 5-HT3 receptors, and on NG108-15 cells and exhibited IC50 values in the low nanomolar or subnanomolar range, as measured by the inhibition of [3H]zacopride binding. The SAR studies detailed herein delineated a number of structural features required for improving affinity. Some of the ligands were employed as 'molecular yardsticks' to probe the spatial dimensions of the lipophilic pockets L1, L2, and L3 in the 5-HT3 receptor cleft, while the 7-OH pyrroloquinoxaline analogue was designed to investigate hydrogen bonding with a putative receptor site H1 possibly interacting with the serotonin hydroxy group. The most active pyrroloquinoxaline derivatives showed subnanomolar affinity for the 5-HT3 receptor. In functional studies ([14C]guanidinium accumulation test in NG108-15 hybrid cells, in vitro) most of the tested compounds showed clear-cut 5-HT3 agonist properties, while some others were found to be partial agonists. Several heteroaromatic systems, bearing N-substituted piperazine moieties, have been explored with respect to 5-HT3 affinity, and novel structural leads for the development of potent and selective central 5-HT3 receptor agonists have been identified. Preliminary pharmacokinetic studies indicate that these compounds easily cross the blood brain barrier (BBB) after systemic administration with a brain/plasma ratio between 2 and 20, unless they bear a highly hydrophilic group on the piperazine ring. None of the tested compounds showed in vivo anxiolytic-like activity, but potential analgesic-like properties have been possibly disclosed for this new class of 5-HT3 receptor agonists.

Original languageEnglish
Pages (from-to)4362-4379
Number of pages18
JournalJournal of Medicinal Chemistry
Volume42
Issue number21
DOIs
Publication statusPublished - 1999

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Serotonin 5-HT3 Receptor Agonists
Receptors, Serotonin, 5-HT3
Structure-Activity Relationship
Thermodynamic properties
Derivatives
Bearings (structural)
Ligands
Histamine H1 Receptors
Pharmacokinetics
Hybrid Cells
Guanidine
Anti-Anxiety Agents
Hydrogen Bonding
Blood-Brain Barrier
Inhibitory Concentration 50
Analgesics
Rats
Brain
Serotonin
Hydrogen bonds

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Pyrroloquinoxaline derivatives as high-affinity and selective 5-HT3 receptor agonists : Synthesis, further structure-activity relationships, and biological studies. / Campiani, Giuseppe; Morelli, Elena; Gemma, Sandra; Nacci, Vito; Butini, Stefania; Hamon, Michel; Novellino, Ettore; Greco, Giovanni; Cagnotto, Alfredo; Goegan, Mara; Cervo, Luigi; Valle, Fabio Dalla; Fracasso, Claudia; Caccia, Silvio; Mennini, Tiziana.

In: Journal of Medicinal Chemistry, Vol. 42, No. 21, 1999, p. 4362-4379.

Research output: Contribution to journalArticle

Campiani, G, Morelli, E, Gemma, S, Nacci, V, Butini, S, Hamon, M, Novellino, E, Greco, G, Cagnotto, A, Goegan, M, Cervo, L, Valle, FD, Fracasso, C, Caccia, S & Mennini, T 1999, 'Pyrroloquinoxaline derivatives as high-affinity and selective 5-HT3 receptor agonists: Synthesis, further structure-activity relationships, and biological studies', Journal of Medicinal Chemistry, vol. 42, no. 21, pp. 4362-4379. https://doi.org/10.1021/jm990151g
Campiani, Giuseppe ; Morelli, Elena ; Gemma, Sandra ; Nacci, Vito ; Butini, Stefania ; Hamon, Michel ; Novellino, Ettore ; Greco, Giovanni ; Cagnotto, Alfredo ; Goegan, Mara ; Cervo, Luigi ; Valle, Fabio Dalla ; Fracasso, Claudia ; Caccia, Silvio ; Mennini, Tiziana. / Pyrroloquinoxaline derivatives as high-affinity and selective 5-HT3 receptor agonists : Synthesis, further structure-activity relationships, and biological studies. In: Journal of Medicinal Chemistry. 1999 ; Vol. 42, No. 21. pp. 4362-4379.
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AU - Nacci, Vito

AU - Butini, Stefania

AU - Hamon, Michel

AU - Novellino, Ettore

AU - Greco, Giovanni

AU - Cagnotto, Alfredo

AU - Goegan, Mara

AU - Cervo, Luigi

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