title: Novel potent and selective central 5-HT3 receptor ligands provided with different intrinsic efficacy. 1. Mapping the central 5-HT3 receptor binding site by arylpiperazine derivatives.
abstract: Synthesis and pharmacological evaluation of a series of condensed quinoline and pyridine derivatives bearing a N-methylpiperazine moiety attached to the 2-position of the quinoline or pyridine nucleus are described. 5-HT receptor binding studies revealed subnanomolar affinity for the 5-HT3 receptor subtype in some of the compounds under study. The most active compound (5b) displayed a Ki value about 1 order of magnitude higher than that of quipazine along with a higher selectivity. The potential 5-HT3 agonist/antagonist activity of four selected compounds was assessed in vitro on 5-HT3 receptor-dependent [14C]guanidinium uptake in NG 108-15 cells. Compound 5j acted as a 5-HT3 agonist in this assay with an EC50 value close to that reported for quipazine, while 5b was a partial agonist with an EC50 value of about 0.25 nM, and compound 5c possessed antagonist properties with an IC50 value (approximately 8 nM) in the same range as those of previously characterized 5-HT3 receptor antagonists. Qualitative and quantitative structure-affinity relationship studies carried out by making use of theoretical molecular descriptors allowed to elucidate the role of the main pharmacophoric components and to develop a model for the interaction of the 5-HT3 ligands related to quipazine with their receptor.
authors.affiliation: Dipartimento Farmaco Chimico Technologico, Università di Siena, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cappelli
authors.forename: M
authors.initials: M
authors.lastname: Anzini
authors.forename: S
authors.initials: S
authors.lastname: Vomero
authors.forename: L
authors.initials: L
authors.lastname: Mennuni
authors.forename: F
authors.initials: F
authors.lastname: Makovec
authors.forename: E
authors.initials: E
authors.lastname: Doucet
authors.forename: M
authors.initials: M
authors.lastname: Hamon
authors.forename: G
authors.initials: G
authors.lastname: Bruni
authors.forename: M R
authors.initials: MR
authors.lastname: Romeo
authors.forename: M C
authors.initials: MC
authors.lastname: Menziani
authors.forename: P G
authors.initials: PG
authors.lastname: De Benedetti
authors.forename: T
authors.initials: T
authors.lastname: Langer
mesh_terms: D000818:Animals; D001554:Benzene / Q000737:chemistry; D001665:Binding Sites; D005910:Glioma; D019791:Guanidine / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009447:Neuroblastoma; D010617:Phenanthridines / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry; D011814:Quipazine / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C111315:6-(4-methyl-1-piperazinyl)--7,8,9,10-tetrahydro-8,10-ethanophenanthridine; C111314:6-(4-methyl-1-piperazinyl)-7,8,9,10-tetrahydrophenanthridine; D010617:Phenanthridines; D010879:Piperazines; D011804:Quinolines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D011814:Quipazine; C037219:quinoline; D001554:Benzene; D019791:Guanidine