title: Conformational Restriction Leading to a Selective CB2 Cannabinoid Receptor Agonist Orally Active Against Colitis.
abstract: The CB2 cannabinoid receptor has been implicated in the regulation of intestinal inflammation. Following on from the promising activity of a series of 4-oxo-1,4-dihydroquinoline-3-carboxamide, we developed constrained analogues based on a 2H-pyrazolo[4,3-c]quinolin-3(5H)-one scaffold, with improved affinity for the hCB2 receptor and had very high selectivity over the hCB1 receptor. Importantly, the lead of this series (26, hCB2: K i = 0.39 nM, hCB1: K i > 3000 nM) was found to protect mice against experimental colitis after oral administration.
authors.affiliation: Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille Nord de France , E.A 4481, IFR 114, 3 rue du Pr. Laguesse, B.P. 83, F-59006 Lille Cedex, France.
authors.forename: Jamal
authors.initials: J
authors.lastname: El Bakali
authors.affiliation: Unité de Chimie Pharmaceutique et de Radiopharmacie, Louvain Drug Research Institute, Université catholique de Louvain , 73 avenue E. Mounier UCL-CMFA (7340), B-1200 Bruxelles, Belgium.
authors.forename: Giulio G
authors.initials: GG
authors.lastname: Muccioli
authors.affiliation: Digestive inflammatory diseases: pathophysiology and development of therapeutic targets. U995 INSERM, Université Lille Nord de France, IFR 114, Amphis J & K, Boulevard du Professeur J. Leclercq, 59045 Lille Cedex, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Body-Malapel
authors.affiliation: Digestive inflammatory diseases: pathophysiology and development of therapeutic targets. U995 INSERM, Université Lille Nord de France, IFR 114, Amphis J & K, Boulevard du Professeur J. Leclercq, 59045 Lille Cedex, France.
authors.forename: Madjid
authors.initials: M
authors.lastname: Djouina
authors.affiliation: Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille Nord de France , E.A 4481, IFR 114, 3 rue du Pr. Laguesse, B.P. 83, F-59006 Lille Cedex, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Klupsch
authors.affiliation: Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille Nord de France , E.A 4481, IFR 114, 3 rue du Pr. Laguesse, B.P. 83, F-59006 Lille Cedex, France.
authors.forename: Alina
authors.initials: A
authors.lastname: Ghinet
authors.affiliation: Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille Nord de France , E.A 4481, IFR 114, 3 rue du Pr. Laguesse, B.P. 83, F-59006 Lille Cedex, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Barczyk
authors.affiliation: Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille Nord de France , E.A 4481, IFR 114, 3 rue du Pr. Laguesse, B.P. 83, F-59006 Lille Cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Renault
authors.affiliation: Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille Nord de France , E.A 4481, IFR 114, 3 rue du Pr. Laguesse, B.P. 83, F-59006 Lille Cedex, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavatte
authors.affiliation: Digestive inflammatory diseases: pathophysiology and development of therapeutic targets. U995 INSERM, Université Lille Nord de France, IFR 114, Amphis J & K, Boulevard du Professeur J. Leclercq, 59045 Lille Cedex, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Desreumaux
authors.affiliation: Unité de Chimie Pharmaceutique et de Radiopharmacie, Louvain Drug Research Institute, Université catholique de Louvain , 73 avenue E. Mounier UCL-CMFA (7340), B-1200 Bruxelles, Belgium.
authors.forename: Didier M
authors.initials: DM
authors.lastname: Lambert
authors.affiliation: Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille Nord de France , E.A 4481, IFR 114, 3 rue du Pr. Laguesse, B.P. 83, F-59006 Lille Cedex, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Millet
keywords: Cannabinoid receptor; colitis; conformational restriction; endocannabinoid; inflammatory bowel disease; quinolone