title: Discovery and pharmacological profile of new 1H-indazole-3-carboxamide and 2H-pyrrolo[3,4-c]quinoline derivatives as selective serotonin 4 receptor ligands.
abstract: Since the discovery of the serotonin 4 receptor (5-HT(4)R), a large number of receptor ligands have been studied. The safety concerns and the lack of market success of these ligands have mainly been attributed to their lack of selectivity. In this study we describe the discovery of N-[(4-piperidinyl)methyl]-1H-indazole-3-carboxamide and 4-[(4-piperidinyl)methoxy]-2H-pyrrolo[3,4-c]quinoline derivatives as new 5-HT(4)R ligands endowed with high selectivity over the serotonin 2A receptor and human ether-a-go-go-related gene potassium ion channel. Within these series, two molecules (11 ab and 12 g) were identified as potent and selective 5-HT(4)R antagonists with good in vitro pharmacokinetic properties. These compounds were evaluated for their antinociceptive action in two analgesia animal models. 12 g showed a significant antinociceptive effect in both models and is proposed as an interesting lead compound as a 5-HT(4)R antagonist with analgesic action.
authors.affiliation: Department of Chemistry, Angelini Santa Palomba Research Center, Piazzale della Stazione snc, 00040 Pomezia, Italy. g.furlotti@angelini.it
authors.forename: Guido
authors.initials: G
authors.lastname: Furlotti
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Alisi
authors.forename: Claudia
authors.initials: C
authors.lastname: Apicella
authors.forename: Alessandra
authors.initials: A
authors.lastname: Capezzone de Joannon
authors.forename: Nicola
authors.initials: N
authors.lastname: Cazzolla
authors.forename: Roberta
authors.initials: R
authors.lastname: Costi
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cuzzucoli Crucitti
authors.forename: Beatrice
authors.initials: B
authors.lastname: Garrone
authors.forename: Alberto
authors.initials: A
authors.lastname: Iacovo
authors.forename: Gabriele
authors.initials: G
authors.lastname: Magarò
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mangano
authors.forename: Gaetano
authors.initials: G
authors.lastname: Miele
authors.forename: Rosella
authors.initials: R
authors.lastname: Ombrato
authors.forename: Luca
authors.initials: L
authors.lastname: Pescatori
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Polenzani
authors.forename: Federica
authors.initials: F
authors.lastname: Rosi
authors.forename: Marco
authors.initials: M
authors.lastname: Vitiello
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Santo
mesh_terms: D000818:Animals; D019295:Computational Biology; D004285:Dogs; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008252:Macaca fascicularis; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects*; D015394:Molecular Structure; D059225:Nociception / Q000187:drug effects*; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D008024:Ligands; D011804:Quinolines; D044422:Receptors, Serotonin, 5-HT4