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Natural products and their synthesis have always fascinated organic chemists, frequently providing the inspiration and testing ground for new synthetic methods. This Review considers examples of natural products that were prepared first synthetically and predicted to be natural products prior to their isolation from nature.

N-methyl-D-aspartate receptors (NMDARs) play a central role in synaptic plasticity, learning and memory. Here the authors describe azobenzene-triazole-glutamate (ATG), a new diffusible photoswitchable agonist that allows precise temporal control over NMDAR activity.

Photochemical reactions are rarely observed at late stages in the biosynthesis of natural products. Here, the authors show that in the case of intricarene, instead of a concerted cycloaddition in the electronic ground state, the key step of the synthesis proceeds photochemically.

Light-based modulation of the microtubule (MT) cytoskeleton is an attractive goal for spatiotemporally-resolved MT studies. Here the authors develop a first generation photoswitchable small molecule MT stabiliser based on paclitaxel, allowing optical control over cellular MT dynamics.

Fatty acids are ancient lipids with numerous functions, from metabolic processes as a source of energy to structural and signalling roles within cell membranes. Here, the authors present azobenzene-modified fatty acids and their application as photoswitchable agonists of the Vanilloid Receptor 1.

A photoisomerizable molecule, quaternary ammonium–azobenzene–quaternary ammonium (QAQ) enables reversible optical silencing of nociceptive neurons. The selective entry of QAQ into active nociceptive neurons allows spatially and temporally precise regulation of nociceptor activity in vitro and in vivo.

A photoswitchable diacylglycerol enables spatiotemporal control of membrane translocation of C1-___domain-containing proteins and protein kinase C activation to modulate calcium oscillations and vesicle release for synaptic transmission.

Loline is a small alkaloid with a deceptively simple-looking structure. Here, a remarkably short synthesis is reported, the key step of which is a transannular aminobromination. The synthesis provides access to loline and to several other members of the loline family in sufficient yield to support a programme investigating the complex biological interactions of these compounds.

Sulfonylureas are widely used anti-diabetic drugs, which promote insulin release by blocking a pancreatic ion channel. Here the authors create a photoswitchable sulfonylurea derivative and use it to control insulin release from cultured cells and isolated pancreatic islets by illumination with blue light.

Light-sensitive ligands can be used to regulate neurobiological receptors with high spatiotemporal precision. Here, the optochemical control of neuronal nicotinic acetylcholine receptors, using both photoswitchable tethered agonists and antagonists, is described. These rationally designed hybrid photoreceptors will facilitate the investigation of the physiological and pathological functions of nicotinic receptors in the brain.

Amiloride is a widely used diuretic that blocks epithelial sodium channels (ENaCs); however, the functional role of the different ENaC isoforms is still poorly understood and no pharmacological tools exist to differentiate between them. Now, photoswitchable amilorides that enable the optical control of ENaCs, and can distinguish between different ENaC isoforms have been developed.

Analysis of the structure of the highly complex yet racemic secondary metabolite epicolactone suggests that it may arise biosynthetically from a cascade similar to that which produces purpurogallin. This led to a synthesis of epicolactone in only eight steps using an intricate reaction cascade.

Structure and functions of the tip of migratory neurons remain elusive. Here, the authors show that the PTPσ-expressing growth cone senses extracellular matrix changes and drives neuronal migration in the injured brain, leading to the functional recovery.

Light in deep tissue can be spatially mapped via magnetic resonance imaging by leveraging liposomal nanoparticles incorporating photosensitive lipids and enclosing paramagnetic molecules.

Cell membranes are dynamic entities that are actively involved in many cellular processes. This Review highlights recent advances in the photopharmacology of phospholipids, exploring the photoswitchable properties of membranes and how they are used in biomedical and biomaterial science applications.

Voltage-gated ion channels respond to alterations in membrane potential and mediate action potential in neurons. A recent study provides new insights into the structure and gating of the Shaker potassium channel.

In this study, the authors develop a photo-pharmacological strategy using a Membrane anchored Photoswitchable orthogonal remotely tethered agonist for the Dopamine receptor (MP-D) to selectively and reversibly modulate the D1R receptor subtype.

A photoswitchable analog of spingosine-1-phosphate (S1P) that allows for modulation of the action of this bioactive lipid exhibits prolonged metabolic stability compared to S1P, activates S1P receptors in cells and mediates nociception in mice.

Open channel blockers are very different in their chemistry and structure. Now GLIC, a bacterial model for pentameric ligand-gated channels, is used to investigate the structural basis of open channel block. The work identifies two extended interaction sites, with large blockers binding to the center of the membrane and small blockers binding to the narrow intracellular region.

To restore sight after retinal degeneration, one approach is to express light-sensitive proteins in remaining cells. Here the authors combine a light-sensitive engineered G protein-coupled receptor and ion channels to restore ON and OFF responses as well as superior visual pattern discrimination.

Rolf Huisgen left us on 26 March 2020, just three months shy of his 100th birthday. His work has had an enormous influence on chemical biology, ranging from new methods for the synthesis of chemical probes to “click chemistry” and its application to in vivo bioconjugation.

This Technical Report describes light-activatable metabotropic glutamate receptors based on synthetic photoswitchable tethered ligands, and demonstrates optogenetic control of G protein–coupled receptor activity in neurons in vivo and ex vivo.

A photoswitchable probe to control Ca²⁺ influx through L-type Ca²⁺ channels is useful in pancreatic β cells and can be employed to modulate beating rate in explanted hearts.

In vertebrates, the excitatory synaptic drive for inducing spinal central pattern generators (CPGs) — which are responsible for generating rhythmic movements — can originate from either supraspinal glutamatergic inputs or from within the spinal cord. A spinal input to the CPG is now identified using a combination of intersectional gene expression and optogenetics in zebrafish larvae; the results reveal that during early development Kolmer–Agduhr cells provide a positive drive to the spinal CPG for spontaneous locomotion.

This paper reports the development of a K⁺-selective glutamate receptor, HyLighter, that reversibly inhibits neuronal activity in response to light. The low light requirement and bi-stability of HyLighter could be useful for studying neural circuitry.

The signalling events leading to insulin release from β-cells are tightly controlled and new techniques are needed to understand the complicated interactions. This Review discusses new optical tools available to further our understanding of β-cell function and insulin release.