title: Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 7. Synthesis and Pharmacological Evaluation of 4-Quinolone-3-carboxamides and 4-Hydroxy-2-quinolone-3-carboxamides as High Affinity Cannabinoid Receptor 2 (CB2R) Ligands with Improved Aqueous Solubility.
abstract: 4-Quinolone-3-carboxamide derivatives have long been recognized as potent and selective cannabinoid type-2 receptor (CB2R) ligands. With the aim to improve their physicochemical properties, basically aqueous solubility, two different approaches were followed, entailing the substitution of the alkyl chain with a basic replacement or scaffold modification to 4-hydroxy-2-quinolone structure. According to the first approach, compound 6d was obtained, showing slightly reduced receptor affinity (K(i) = 60 nM) compared to the lead compound 4 (0.8 nM) but greatly enhanced solubility (400-3400 times depending on the pH of the medium). On the other hand, shifting from 4-quinolone to 4-hydroxy-2-quinolone structure enabled the discovery of a novel class of CB2R ligands, such as 7b and 7c, characterized by K(i) < 1 nM and selectivity index [SI = K(i)(CB1R)/K(i)(CB2R)] > 1300. At pH 7.4, compound 7c resulted by 100-fold more soluble than 4.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mugnaini
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Brizzi
authors.affiliation: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche , Via dei Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.affiliation: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche , Via dei Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Allarà
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Lamponi
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.affiliation: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche , Via dei Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D008024:Ligands; D015363:Quinolones; D043885:Receptor, Cannabinoid, CB2; D014867:Water