Novel, Potent, and Selective 5-HT3 Receptor Antagonists Based on the Arylpiperazine Skeleton: Synthesis, Structure, Biological Activity, and Comparative Molecular Field Analysis Studies

• Published in: Journal of medicinal chemistry Vol. 38; no. 14; pp. 2692 - 2704
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.07.1995; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Chemistry, Medicinal; Crystallography, X-Ray; Guinea Pigs; In Vitro Techniques; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Male; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Piperazines - chemistry; Rats; Rats, Sprague-Dawley; Science & Technology; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - chemistry; Serotonin Antagonists - pharmacology; Serotoninergic system; Structure-Activity Relationship; Tumor Cells, Cultured; ASSAY; LIGANDS; HIGH-AFFINITY; MEMBRANES; SITES; RAT-BRAIN; D-FENFLURAMINE; DERIVATIVES; BINDING; Rat; Nitrogen heterocycle; Rodentia; Central nervous system; Quinoline derivatives; Tetracyclic compound; In vitro; Modeling; In vivo; Vertebrata; Biological fixation; Three dimensional model; Mammalia; Structure activity relation; Animal; Molecular model; Affinity; Aromatic compound; Antagonist; Piperazine derivatives; Chemical synthesis; Brain (vertebrata); Oxygen nitrogen heterocycle; 5-HT3 receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00014a021

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 K-i 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 r(2), 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 pK(i) values. The steric and electrostatic features of the CoMFA-derived model are presented as standard coefficient contour maps of steric and electrostatic fields.