Optical Control of Dopamine D2-like Receptors with Cell-Specific Fast-Relaxing Photoswitches.

Dopamine D2-like receptors (D2R, D3R, and D4R) control diverse physiological and behavioral functions and are important targets for the treatment of a variety of neuropsychiatric disorders. Their complex distribution and activation kinetics in the brain make it difficult to target specific receptor populations with sufficient precision. We describe a new toolkit of light-activatable, fast-relaxing, covalently taggable chemical photoswitches that fully activate, partially activate, or block D2-like receptors. This technology combines the spatiotemporal precision of a photoswitchable ligand (P) with cell type and spatial specificity of a genetically encoded membrane anchoring protein (M) to which the P tethers. These tools set the stage for targeting endogenous D2-like receptor signaling with molecular, cellular, and spatiotemporal precision using only one wavelength of light.

Optopharmacological tools for precise spatiotemporal control of oxytocin signaling in the central nervous system and periphery.

Oxytocin is a neuropeptide critical for maternal physiology and social behavior, and is thought to be dysregulated in several neuropsychiatric disorders. Despite the biological and neurocognitive importance of oxytocin signaling, methods are lacking to activate oxytocin receptors with high spatiotemporal precision in the brain and peripheral mammalian tissues. Here we developed and validated caged analogs of oxytocin which are functionally inert until cage release is triggered by ultraviolet light. We examined how focal versus global oxytocin application affected oxytocin-driven Ca2+ wave propagation in mouse mammary tissue. We also validated the application of caged oxytocin in the hippocampus and auditory cortex with electrophysiological recordings in vitro, and demonstrated that oxytocin uncaging can accelerate the onset of mouse maternal behavior in vivo. Together, these results demonstrate that optopharmacological control of caged peptides is a robust tool with spatiotemporal precision for modulating neuropeptide signaling throughout the brain and body.

A concise synthesis of tetrodotoxin.

Tetrodotoxin (TTX) is a neurotoxic natural product that is an indispensable probe in neuroscience, a biosynthetic and ecological enigma, and a celebrated target of synthetic chemistry. Here, we present a stereoselective synthesis of TTX that proceeds in 22 steps from a glucose derivative. The central cyclohexane ring of TTX and its α-tertiary amine moiety were established by the intramolecular 1,3-dipolar cycloaddition of a nitrile oxide, followed by alkynyl addition to the resultant isoxazoline. A ruthenium-catalyzed hydroxylactonization set the stage for the formation of the dioxa-adamantane core. Installation of the guanidine, oxidation of a primary alcohol, and a late-stage epimerization gave a mixture of TTX and anhydro-TTX. This synthetic approach could give ready access to biologically active derivatives.

Photoswitchable Serotonins for Optical Control of the 5-HT2A Receptor.

Serotonin receptors play central roles in neuromodulation and are critical drug targets for psychiatric disorders. Optical control of serotonin receptor subtypes has the potential to greatly enhance our understanding of the spatiotemporal dynamics of receptor function. While other neuromodulatory receptors have been successfully rendered photoswitchable, reversible photocontrol of serotonin receptors has not been achieved, representing a major gap in GPCR photopharmacology. Herein, we develop the first tools that allow for such control. Azo5HT-2 shows light-dependent 5-HT2A R agonism, with greater activity in the cis-form. Based on docking and test compound analysis, we also develop photoswitchable orthogonal, remotely-tethered ligands (PORTLs). These BG-Azo5HTs provide rapid, reversible, and repeatable optical control following conjugation to SNAP-tagged 5-HT2A R. Overall, this study provides a foundation for the broad extension of photopharmacology to the serotonin receptor family.

Natural product anticipation through synthesis.

Natural product synthesis remains one of the most vibrant and intellectually rewarding areas of chemistry, although the justifications for pursuing it have evolved over time. In the early years, the emphasis lay on structure elucidation and confirmation through synthesis, as exemplified by celebrated studies on cocaine, morphine, strychnine and chlorophyll. This was followed by a phase where the sheer demonstration that highly complex molecules could be recreated in the laboratory in a rational manner was enough to justify the economic expense and intellectual agonies of a synthesis. Since then, syntheses of natural products have served as platforms for the demonstration of elegant strategies, for inventing new methodology 'on the fly' or to demonstrate the usefulness and scope of methods established with simpler molecules. We now add another aspect that we find fascinating, viz. 'natural product anticipation'. In this Review, we survey cases where the synthesis of a compound in the laboratory has preceded its isolation from nature. The focus of our Review lies on examples where this anticipation of a natural product has triggered a successful search or where synthesis and isolation have occurred independently. Finally, we highlight cases where a potential natural product structure has been suggested as a result of synthetic endeavours but not yet confirmed by isolation, inviting further collaborations between synthetic and natural product chemists.

Selective Photoswitchable Allosteric Agonist of a G Protein-Coupled Receptor.

G protein-coupled receptors (GPCRs) are the most common targets of drug discovery. However, the similarity between related GPCRs combined with the complex spatiotemporal dynamics of receptor activation in vivo has hindered drug development. Photopharmacology offers the possibility of using light to control the location and timing of drug action by incorporating a photoisomerizable azobenzene into a GPCR ligand, enabling rapid and reversible switching between an inactive and active configuration. Recent advances in this area include (i) photoagonists and photoantagonists that directly control receptor activity but are nonselective because they bind conserved sites, and (ii) photoallosteric modulators that bind selectively to nonconserved sites but indirectly control receptor activity by modulating the response to endogenous ligand. In this study, we designed a photoswitchable allosteric agonist that targets a nonconserved allosteric site for selectivity and activates the receptor on its own to provide direct control. This work culminated in the development of aBINA, a photoswitchable allosteric agonist that selectively activates the Gi/o-coupled metabotropic glutamate receptor 2 (mGluR2). aBINA is the first example of a new class of precision drugs for GPCRs and other clinically important signaling proteins.

Optical Control of Cytokine Production Using Photoswitchable Galactosylceramides.

α-Galactosylceramides are glycosphingolipids that show promise in cancer immunotherapy. After presentation by CD1d, they activate natural killer T cells (NKT), which results in the production of a variety of pro-inflammatory and immunomodulatory cytokines. Herein, we report the synthesis and biological evaluation of photochromic derivatives of KRN-7000, the activity of which can be modulated with light. Based on established structure-activity relationships, we designed photoswitchable analogues of this glycolipid that control the production of pro-inflammatory cytokines, such as IFN-γ. The azobenzene derivative α-GalACer-4 proved to be more potent than KRN-7000 itself when activated with 370 nm light. Photolipids of this type could improve our mechanistic understanding of cytokine production and could open new directions in photoimmunotherapy.

A Versatile Bis-Allylboron Reagent for the Stereoselective Synthesis of Chiral Diols.

Allylboron reagents are popular in synthesis owing to their versatility and the predictable stereochemical outcomes of their reactions with carbonyl compounds. Herein, we describe the synthesis of (Z,Z)-hexadienyl bis-boronate 1, a configurationally stable, crystalline, and easy to handle compound, which represents a class of bis-allylic boron reagents with heretofore untapped synthetic potential. In combination with a chiral phosphoric acid catalyst, the reagent can be employed for the enantioselective allyl transfer reaction to a variety of one-pot transformations, enabling swift access to functionalized 1,n-diols. The in situ conversion of the reagent into the corresponding bis-borinic ester allows for the direct and diastereoselective two-fold allyl transfer to aldehydes. This affords C2 - or Ci -symmetric stereotetrads containing a 1,4-diol moiety for natural product synthesis. The usefulness of our method was demonstrated with a short synthesis of the lignan (±)-neo-olivil.