Rational Remodeling of Atypical Scaffolds for the Design of Photoswitchable Cannabinoid Receptor Tools

Abstract

Azobenzene-embedded photoswitchable ligands are the widely used chemical tools in photopharmacological studies. Current approaches to azobenzene introduction rely mainly on the isosteric replacement of typical azologable groups. However, atypical scaffolds may offer more opportunities for photoswitch remodeling, which are chemically in an overwhelming majority. Herein, we investigate the rational remodeling of atypical scaffolds for azobenzene introduction, as exemplified in the development of photoswitchable ligands for the cannabinoid receptor 2 (CB2). Based on the analysis of residue-type clusters surrounding the binding pocket, we conclude that among the three representative atypical arms of the CB2 antagonist, AM10257, the adamantyl arm is the most appropriate for azobenzene remodeling. The optimizing spacer length and attachment position revealed AzoLig 9 with excellent thermal bistability, decent photopharmacological switchability between its two configurations, and high subtype selectivity. This structure-guided approach gave new impetus in the extension of new chemical spaces for tool customization for increasingly diversified photo-pharmacological studies and beyond.

Hypothesis-Driven, Structure-Based Design in Photopharmacology: The Case of eDHFR Inhibitors

“…Moreover, using one isomer to target a charge-assisted hydrogen bond between a carboxylic acid and an arginine has been recently implemented in photopharmacology . However, targeting a particular interaction with one of the two isomers is still an underexplored approach for reversible photopharmacology. , We designed two compounds, exploring both meta and para substitution on the outer benzene ring (Figure B). We first evaluated our hypothesis computationally, and IFD poses and subsequent MD simulations suggested that compound 11 could engage in the desired salt bridge only in the case of the cis -isomer (Figure A).…”

“…Very recently, the atypical azologization of an adamantyl group has been reported in the design of a photoswitchable cannabinoid receptor ligand. 24 However, most drugs do not feature cisoid substructures that can be substituted, thus highlighting the need for a strategy with a broader utility.…”

“…A partial solution for the rational design of cis -on photoswitchable drugs is provided by the azologization of cisoid azosteres, that is, moieties that are geometrically and electrostatically similar to cis -azobenzene: Azologization of cis -stilbene in combretastatin A-4, N -methylbenzilaniline in methotrexate, , benzophenone in a CRY1 activator, and biaryl sulfonamide in kinase, phospholipase and histone deacetylase inhibitors , resulted in cis- on ligands. Very recently, the atypical azologization of an adamantyl group has been reported in the design of a photoswitchable cannabinoid receptor ligand . However, most drugs do not feature cisoid substructures that can be substituted, thus highlighting the need for a strategy with a broader utility.…”

Development of an Indole-Amide-Based Photoswitchable Cannabinoid Receptor Subtype 1 (CB1R) “Cis-On” Agonist

“…27,28 Recently, Tao et al have described the design of azosters derived from the pharmacophoric structure of the CB 2 R antagonist AM10257. 29 Using a rational remodeling approach, they replaced the adamantyl group of the parent compound with an azobenzene moiety, thereby creating a new photoligand with an affinity for CB 2 R in its cis-form more than 40 times higher than its trans-form. These results opened up new possibilities for photoligand design through a novel structureguided approach.…”

“…Subsequently, Carreira, Frank, and co-workers described the synthesis of highly selective CB 2 R agonists coupled to fluorescent and photoswitchable moieties. This new class of hybrid photo-ligands has the ability to monitor CB 2 R signaling by controlling calcium release in real time. , Recently, Tao et al have described the design of azosters derived from the pharmacophoric structure of the CB 2 R antagonist AM10257 . Using a rational remodeling approach, they replaced the adamantyl group of the parent compound with an azobenzene moiety, thereby creating a new photoligand with an affinity for CB 2 R in its cis -form more than 40 times higher than its trans -form.…”