Toward the design of cannabinoid CB₁ receptor inverse agonists and neutral antagonists

Abstract

The cannabinoid CB 1 receptor belongs to Class A of the G-protein-coupled receptor (GPCR) family. The high constitutive activity of CB 1 facilitates inverse agonism at this receptor, and CB 1 inverse agonists/antagonists have recently been considered for the treatment of obesity and metabolic syndrome. GPCRs are assumed to have a common topology and to share a common molecular activation mechanism involving their intracellular domains. However, each individual receptor will also have a molecular switch within the ligand binding pocket that is a noncovalent intramolecular interaction in the basal state of the GPCR that must be disrupted to achieve an active state or stabilized to maintain the inactive state. Knowledge of the molecular switch within the ligand binding pocket can greatly facilitate the rational design of inverse agonists and neutral antagonists. This review begins with a brief review on the CB 1 receptor and its ligands. The review then focuses on the experimental literature on GPCR structure and activation in Class A receptors. The identification of the molecular switch region in the ligand binding pocket of CB 1 (F3.36/W6.48) is discussed and the combined mutation and modeling studies that have led to the identification of interactions key to the inverse agonism of SR141716A are presented. Finally, the development of the first CB 1 neutral antagonists based on these modeling/mutation results is discussed. Drug Dev Res 70 : 585-600, 2009.

Metabolic Profiling of CB1 Neutral Antagonists

“…In addition to the H-bond between the C-3 hydrazide moiety and the wild-type receptor’s 3.28 lysine contributing to the strength of the ligands affinity for the receptor binding site, there are also aromatic stacking interactions that enable all these ligands to bind with nanomolar affinity and to stabilize receptor conformations (Hurst et al, 2002, 2006; Reggio, 2009). …”

“…Other classes of CB1R regulators in the form of neutral antagonists, that do not change basal CB1R activity, have been revealed (Pan et al, 1998) and are the subject of study (Hurst et al, 2002, 2006; Pertwee, 2005a; Reggio, 2009; Silvestri & Di Marzo, 2012) and development (Alonso et al, 2012; Argueta & DiPatrizio, 2017; Bostroem et al, 2010; Brents et al, 2012; Franks et al, 2014; Fride et al, 2007; Greig & Ross, 2010; Kangas et al, 2013; Makriyannis & Vemuri, 2008; Ruiu et al, 2003; Vela Hernandez & Yenes Minguez, 2009; Wargent et al, 2013; Wiley et al, 2011). …”

Exploring the Ligand Efficacy of Cannabinoid Receptor 1 (CB1) using Molecular Dynamics Simulations

“…Depending on the biological response of CB1, ligands with different efficacy profiles and therapeutic effects were largely classified into three classes: agonists, antagonists, and inverse agonists 10 – 12 . CB1 agonists have potential for therapeutic applications in pain, inflammation, and neurodegenerative disorders 13 , 14 .…”

Ligand-specific homology modeling of human cannabinoid (CB1) receptor

“…356) to alanine significantly reduced the binding of SR141716A to the CB1 receptor[9,54,55]. Studies suggest that the interaction between F3.36(200) and W6.48(356), representing a "toggle switch", is an important constrain that keeps CB1 receptor in its inactive state and the salt bridge between K3.28(192) and D6.58(366) stabilizes CB1 in its inactive state[54,55].…”