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

Abstract

The cannabinoid receptor 2 (CB2R) has high, unexploited therapeutic potential in several central nervous system disorders due to its involvement in neuroinflammatory processes and pathologies like neurodegeneration. Dualsteric/bitopic ligands are currently developed to achieve receptor subtype selectivity and biased signaling. To obtain a molecular tool compound with photoswitchable potential dualsteric properties, we applied two different approaches to link a positive allosteric modulator with an orthosteric agonist via a photochromic unit. We characterized the photophysical properties of all compounds and determined efficacy in internalization, calcium mobilization, and BRET studies. We report the first potentially dualsteric photoswitchable ligand for studying molecular mechanisms of CB2R-associated pathologies. Compound 17- para is a submicromolar “cis-on” agonist with >10-fold higher potency compared to its trans photoisomer and allows high spatiotemporal control of CB2R activation.

Ideal efficacy photoswitches for TRPC4/5 channels harness high potency for spatiotemporally-resolved control of TRPC function in live tissues

“…Key contributions include those of Decker, Leurs, Gorostiza, and coworkers (discussed in Supporting Note 2). [42][43][44][45][46][47][48][49][50][51] With the exception of Leurs' micromolar chemokine photoswitch ligand VUF16216, 43,48 efficacy switching on the other known targets can be considered "non-ideal" in that (a) the ligand efficacies were switched between moreand less-activating, rather than activating and inhibiting, and (b) the isomers' affinity was rather different, which compromises the concentration-independence of ideal efficacy switching. It is also certain that other efficacy switches have been created, but simply not reported as such; e.g., we also published a reagent with excellent dynamic range of bioactivity photocontrol despite its E⇆Z photoswitching incompleteness, but had not understood the full consequences of that performance at the time 34 (while re-parsing recent photopharmacology papers, we believe we have found many more instances of unsuspected efficacy switches; Supporting Note 2 discusses this further with some examples from Fuchter, Groschner, Pepperberg, Trauner, etc [52][53][54][55][56] ).…”