In This Issue pubs.acs.org/chemneuro
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FLIPPING THE SWITCH ON TRANSPORTERS
designed to engage the VBS of TRPV1, derived from a tricyclic spirolactone scaffold. Notably, compounds lacking the few chemical functionalities thought to be essential for TRPV1 engagement, including a vanilloid-like domain, were explored. The compounds instead retained only a single olefin moiety thought to be a key functionality in known TRPV1 agonists. Nevertheless, this unique class of compounds was able to interface with TRPV1 through the VBS domain, challenging the conventional wisdom of pharmacological profiling and leading to new insights into the mechanisms of broad TRPV1 target engagement.
Glutamate neurotransmission and maintenance of glutamate homeostasis are critical mechanisms for synaptic function, mediated in part by excitatory amino acid transporters (EAATs). EAATs rapidly remove glutamate from the synaptic cleft following neurotransmission, preventing excitoxicity and neuronal damage. The ability to further probe and potentially control the physiological mechanisms of EAAT function can provide valuable insight into these important neural functions. In this issue, Cheng and co-workers (DOI: 10.1021/ acschemneuro.7b00072) build on their previous work developing synthetic azobenzene photoswitches that allow for photocontrol of biological systems. Here, the authors describe the development of a new azobeneze photoswitch, dubbed ATT, that enables precise and reversible control of EAAT activity. ATT can be reversibly photoisomerized to either the cis- (λ = 350 nm irradiation) or trans- (λ = 450 nm irradiation) configurations. ATT was found to bind several mammalian EAATs and could be reversibly switched between the transconfiguration, binding with high affinity, and the cisconfiguration, binding with low affinity, using different wavelengths of light. This dual binding mode enabled photocontrolled modulation of glutamate transport.
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The use and abuse of psychoactive synthetic cannabinoids (SCs) is widespread throughout the world. Most contain a 1pentyl-1-H substituted indole or indazole moiety, and unlike THC, which only contains one psychoactive metabolite, several metabolites of SCs are hypothesized to retain cannabimimetic activity. However, limited studies have been carried out on the pharmacology of phase 1 SC metabolites. In this issue, Longworth et al. (DOI: 10.1021/acschemneuro.7b00116) synthesized a series of selected SCs and their known metabolites, developing novel synthetic routes to these compounds and characterizing their pharmacology. They evaluated the in vitro ability to bind the cannabinoid CB1 and CB2 receptor using a fluorometric assay of membrane potential, establishing the structure−activity relationships of synthetic cannabinoids and their metabolites.
HOLD THE PEPPER: A NOVEL CLASS OF AGONISTS FOR A CAPSAICIN RECEPTOR
The transient receptor potential vanilloid-1 (TRPV1) plays a key role in mechanisms involved in the pain response, detecting a variety of pain-inducing stimuli such as heat, acid, and toxins. One group of ligands that engages and activates TRPV1 is, as the name suggests, vanilloids. Vanilloids include pain-evoking molecules, with one of the most well-known being capsaicin (found in pepper). Activation of TRVP1 via vanilloid binding mediates the pain response; the development of inhibitors that engage the vanilloid binding site (VBS) represent new potential treatment options for neuropathic pain. Here, Mostinski et al., (DOI: 10.1021/acschemneuro.7b00127) analyze the chemical architecture of these inhibitors, which contain few common chemical motifs and no clear functional domains. Finding only a few common molecular domains among this broad class of compounds, the authors instead synthesized a novel family of molecules © 2017 American Chemical Society
HIGH TIMES FOR SYNTHETIC CANNABINOIDS
Published: August 16, 2017 1637
DOI: 10.1021/acschemneuro.7b00296 ACS Chem. Neurosci. 2017, 8, 1637−1637
