Bridging the Binding Sites: Dualsteric Ligands for the Cannabinoid 2 Receptor (CB₂R)

Abstract

The cannabinoid receptor subtype 2 (CB 2 R) is rapidly upregulated in neuroinflammatory processes and respective agonists have a high potential to combat several central nervous system disorders related to neuroinflammation and neurodegeneration. As a new strategy for ligand design, dualsteric binding is applied by chemically combining a positive allosteric modulator with an orthosteric ligand. The resulting two sets of potential dualsteric (or bitopic) ligands with different chain lengths of two to five methylene groups are evaluated in [ 3 H]CP55940 binding studies to determine receptor affinity at CB 1 R and CB 2 R. Calcium mobilization, receptor endocytosis and BRET assays determine their efficacy and identify compounds of set B to act as agonists with efficacy higher than the reference compound in G protein mediated calcium signaling. Pharmacological evaluation and docking studies support the dualsteric nature of binding of the herein presented compounds.

Bridging the Binding Sites 2.0: Photoswitchable Dualsteric Ligands for the Cannabinoid 2 Receptor

“…Linking at the meta position of the PAM benzyl was also investigated, as the optimal chain length for para connection (propylene linker) for the parent compound (B3) displayed comparable effects as meta connection with a butylene linker (B4m). 13 The two series of compounds were synthesized in convergent synthetic routes. Fragment 3 was synthesized in four steps according to literature procedures.…”

“…This approach is especially promising for pathologies where the endogenous ligand is absent, like for acetylcholine deficiency in neurodegenerative diseases like AD . Two different approaches toward dualsteric heterobivalent ligands for CB 2 R have very recently been described by Gado et al and us. − Gado et al discovered the first CB 2 R-selective PAM ( 1 , Figure ) and recently also obtained the first dualsteric ligand by linking their PAM to a structurally related orthosteric ligand. , Their dualsteric lead compound had anti-inflammatory effects in a human microglial cell inflammatory model and antinociceptive activity in vivo , observed in an experimental mouse model of neuropathic pain . In a recent work, we synthesized the dualsteric CB 2 R ligand B3 ( cf.…”

Designing drugs and chemical probes with the dualsteric approach

“…Molecular docking is one of the most widely used approaches for the validation of dualsteric binding modes, probably due to its lower cost. 54,57,58,64,65,70–72,76–80,82–86,88,92–95,98–100,103,109,114,115,117,121–123,126,127,129,131,133,134,137,138,140,160,162,163,165–167,169,170,172,176,177,182,184,186,198,199,252 However, the setting of the docking box, which restricts the position of searching, should be taken great care of. If the box is narrowed to only the orthosteric and allosteric site or interaction between a certain residue and the modulator is forced, the validation could not be reliable because the dualsteric binding pose is used as prior.…”

“…After a manual filtering, 133 research articles focusing on identifications of novel dualsteric modulators were found. Modulators targeting GPCR 50,53,56–137 or kinase 138–157 account for more than three quarters (Fig. 5).…”

“…GPCR itself has accommodated 62.4% targets of reports. 50,53,56–137 GPCR is a class of 7-transmembrane (7TM) proteins decorated on the cell membrane for transduction amplification of exterior signals into cells. 189 They are vital in many physiological processes and are therefore popular drug targets for a series of diseases like cancers and neurological disorders.…”