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: Jamal El Bakali, Giulio G Muccioli, Mathilde Body-Malapel, Madjid Djouina, Frédérique Klupsch, Alina Ghinet, Amélie Barczyk, Nicolas Renault, Philippe Chavatte, Pierre Desreumaux, Didier M Lambert, Régis Millet
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 6 Issue 2 Pg. 198-203 (Feb 12 2015) ISSN: 1948-5875 [Print] United States
• PMID: 25699149 (Publication Type: Journal Article)