Novel, potent, and selective 5-HT3 receptor antagonists based on the arylpiperazine skeleton: Synthesis, structure, biological activity, and comparative molecular field analysis studies

Maurizio Anzini, Andrea Cappelli, Salvatore Vomero, Gianluca Giorgi, Thierry Langer, Michel Hamon, Nacera Merahi, Boris M. Emerit, Alfredo Cagnotto, Malgorzata Skorupska, Tiziana Mennini, Julia C. Pinto

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

Synthesis and pharmacological evaluation of a series of condensed quinoline derivatives bearing a basic nitrogen on piperazine or [(dimethylamino)ethyl]thio moieties attached at the 2-position of the quinoline nucleus are described. 5-HT receptor binding studies revealed, for most of the compounds studied, nanomolar affinity for the 5-HT3 receptor subtype. The most active compound, benzopyrano[3,4-c]quinoline derivative 5f, displayed a Ki value very similar to that reported for quipazine along with an improved selectivity. Functional and in vivo testing carried out on three selected compounds showed that 5f,j,n are potent 5-HT3 receptor antagonists with potencies in the same range as the best known 5-HT3 receptor antagonists ondansetron, tropisetron, and zacopride. The crystal and molecular structures of compounds 5f,j,n were determined by single-crystal X-ray diffraction and used as starting structures for molecular modeling studies. Comparative molecular field analysis (CoMFA) was applied to binding constants of compounds 5a-p and 6a-h. The cross-validated r2, derived from partial least-squares calculations, indicated a good predictive capacity for affinity values in the series of compounds investigated. Evidence for the prediction capacity is provided in the form of plots of actual vs predicted pKi values. The steric and electrostatic features of the CoMFA-derived model are presented as standard coefficient contour maps of steric and electrostatic fields.

Original languageEnglish
Pages (from-to)2692-2704
Number of pages13
JournalJournal of Medicinal Chemistry
Volume38
Issue number14
Publication statusPublished - 1995

Fingerprint

Serotonin 5-HT3 Receptor Antagonists
Receptors, Serotonin, 5-HT3
Bioactivity
Skeleton
tropisetron
Molecular Structure
Static Electricity
Bearings (structural)
Quipazine
Derivatives
Ondansetron
Molecular modeling
Serotonin Receptors
Least-Squares Analysis
X-Ray Diffraction
Molecular structure
Electrostatics
Nitrogen
Crystal structure
Electric fields

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Novel, potent, and selective 5-HT3 receptor antagonists based on the arylpiperazine skeleton : Synthesis, structure, biological activity, and comparative molecular field analysis studies. / Anzini, Maurizio; Cappelli, Andrea; Vomero, Salvatore; Giorgi, Gianluca; Langer, Thierry; Hamon, Michel; Merahi, Nacera; Emerit, Boris M.; Cagnotto, Alfredo; Skorupska, Malgorzata; Mennini, Tiziana; Pinto, Julia C.

In: Journal of Medicinal Chemistry, Vol. 38, No. 14, 1995, p. 2692-2704.

Research output: Contribution to journalArticle

Anzini, M, Cappelli, A, Vomero, S, Giorgi, G, Langer, T, Hamon, M, Merahi, N, Emerit, BM, Cagnotto, A, Skorupska, M, Mennini, T & Pinto, JC 1995, 'Novel, potent, and selective 5-HT3 receptor antagonists based on the arylpiperazine skeleton: Synthesis, structure, biological activity, and comparative molecular field analysis studies', Journal of Medicinal Chemistry, vol. 38, no. 14, pp. 2692-2704.
Anzini, Maurizio ; Cappelli, Andrea ; Vomero, Salvatore ; Giorgi, Gianluca ; Langer, Thierry ; Hamon, Michel ; Merahi, Nacera ; Emerit, Boris M. ; Cagnotto, Alfredo ; Skorupska, Malgorzata ; Mennini, Tiziana ; Pinto, Julia C. / Novel, potent, and selective 5-HT3 receptor antagonists based on the arylpiperazine skeleton : Synthesis, structure, biological activity, and comparative molecular field analysis studies. In: Journal of Medicinal Chemistry. 1995 ; Vol. 38, No. 14. pp. 2692-2704.
@article{e38208e368dc428abf8105a118e84a6d,
title = "Novel, potent, and selective 5-HT3 receptor antagonists based on the arylpiperazine skeleton: Synthesis, structure, biological activity, and comparative molecular field analysis studies",
abstract = "Synthesis and pharmacological evaluation of a series of condensed quinoline derivatives bearing a basic nitrogen on piperazine or [(dimethylamino)ethyl]thio moieties attached at the 2-position of the quinoline nucleus are described. 5-HT receptor binding studies revealed, for most of the compounds studied, nanomolar affinity for the 5-HT3 receptor subtype. The most active compound, benzopyrano[3,4-c]quinoline derivative 5f, displayed a Ki value very similar to that reported for quipazine along with an improved selectivity. Functional and in vivo testing carried out on three selected compounds showed that 5f,j,n are potent 5-HT3 receptor antagonists with potencies in the same range as the best known 5-HT3 receptor antagonists ondansetron, tropisetron, and zacopride. The crystal and molecular structures of compounds 5f,j,n were determined by single-crystal X-ray diffraction and used as starting structures for molecular modeling studies. Comparative molecular field analysis (CoMFA) was applied to binding constants of compounds 5a-p and 6a-h. The cross-validated r2, derived from partial least-squares calculations, indicated a good predictive capacity for affinity values in the series of compounds investigated. Evidence for the prediction capacity is provided in the form of plots of actual vs predicted pKi values. The steric and electrostatic features of the CoMFA-derived model are presented as standard coefficient contour maps of steric and electrostatic fields.",
author = "Maurizio Anzini and Andrea Cappelli and Salvatore Vomero and Gianluca Giorgi and Thierry Langer and Michel Hamon and Nacera Merahi and Emerit, {Boris M.} and Alfredo Cagnotto and Malgorzata Skorupska and Tiziana Mennini and Pinto, {Julia C.}",
year = "1995",
language = "English",
volume = "38",
pages = "2692--2704",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "14",

}

TY - JOUR

T1 - Novel, potent, and selective 5-HT3 receptor antagonists based on the arylpiperazine skeleton

T2 - Synthesis, structure, biological activity, and comparative molecular field analysis studies

AU - Anzini, Maurizio

AU - Cappelli, Andrea

AU - Vomero, Salvatore

AU - Giorgi, Gianluca

AU - Langer, Thierry

AU - Hamon, Michel

AU - Merahi, Nacera

AU - Emerit, Boris M.

AU - Cagnotto, Alfredo

AU - Skorupska, Malgorzata

AU - Mennini, Tiziana

AU - Pinto, Julia C.

PY - 1995

Y1 - 1995

N2 - Synthesis and pharmacological evaluation of a series of condensed quinoline derivatives bearing a basic nitrogen on piperazine or [(dimethylamino)ethyl]thio moieties attached at the 2-position of the quinoline nucleus are described. 5-HT receptor binding studies revealed, for most of the compounds studied, nanomolar affinity for the 5-HT3 receptor subtype. The most active compound, benzopyrano[3,4-c]quinoline derivative 5f, displayed a Ki value very similar to that reported for quipazine along with an improved selectivity. Functional and in vivo testing carried out on three selected compounds showed that 5f,j,n are potent 5-HT3 receptor antagonists with potencies in the same range as the best known 5-HT3 receptor antagonists ondansetron, tropisetron, and zacopride. The crystal and molecular structures of compounds 5f,j,n were determined by single-crystal X-ray diffraction and used as starting structures for molecular modeling studies. Comparative molecular field analysis (CoMFA) was applied to binding constants of compounds 5a-p and 6a-h. The cross-validated r2, derived from partial least-squares calculations, indicated a good predictive capacity for affinity values in the series of compounds investigated. Evidence for the prediction capacity is provided in the form of plots of actual vs predicted pKi values. The steric and electrostatic features of the CoMFA-derived model are presented as standard coefficient contour maps of steric and electrostatic fields.

AB - Synthesis and pharmacological evaluation of a series of condensed quinoline derivatives bearing a basic nitrogen on piperazine or [(dimethylamino)ethyl]thio moieties attached at the 2-position of the quinoline nucleus are described. 5-HT receptor binding studies revealed, for most of the compounds studied, nanomolar affinity for the 5-HT3 receptor subtype. The most active compound, benzopyrano[3,4-c]quinoline derivative 5f, displayed a Ki value very similar to that reported for quipazine along with an improved selectivity. Functional and in vivo testing carried out on three selected compounds showed that 5f,j,n are potent 5-HT3 receptor antagonists with potencies in the same range as the best known 5-HT3 receptor antagonists ondansetron, tropisetron, and zacopride. The crystal and molecular structures of compounds 5f,j,n were determined by single-crystal X-ray diffraction and used as starting structures for molecular modeling studies. Comparative molecular field analysis (CoMFA) was applied to binding constants of compounds 5a-p and 6a-h. The cross-validated r2, derived from partial least-squares calculations, indicated a good predictive capacity for affinity values in the series of compounds investigated. Evidence for the prediction capacity is provided in the form of plots of actual vs predicted pKi values. The steric and electrostatic features of the CoMFA-derived model are presented as standard coefficient contour maps of steric and electrostatic fields.

UR - http://www.scopus.com/inward/record.url?scp=0029052166&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029052166&partnerID=8YFLogxK

M3 - Article

C2 - 7629808

AN - SCOPUS:0029052166

VL - 38

SP - 2692

EP - 2704

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 14

ER -