Synthesis of Photoswitchable Δ9-Tetrahydrocannabinol Derivatives Enables Optical Control of Cannabinoid Receptor 1 Signaling

J Am Chem Soc. 2017 Dec 20;139(50):18206-18212. doi: 10.1021/jacs.7b06456. Epub 2017 Dec 12.

Abstract

The cannabinoid receptor 1 (CB1) is an inhibitory G protein-coupled receptor abundantly expressed in the central nervous system. It has rich pharmacology and largely accounts for the recreational use of cannabis. We describe efficient asymmetric syntheses of four photoswitchable Δ9-tetrahydrocannabinol derivatives (azo-THCs) from a central building block 3-Br-THC. Using electrophysiology and a FRET-based cAMP assay, two compounds are identified as potent CB1 agonists that change their effect upon illumination. As such, azo-THCs enable CB1-mediated optical control of inwardly rectifying potassium channels, as well as adenylyl cyclase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Biological Assay
  • Brain / drug effects
  • Cannabinoids / chemistry*
  • Dronabinol / chemistry*
  • Drug Design
  • Electrophysiological Phenomena
  • Optics and Photonics
  • Photosensitizing Agents / chemistry*
  • Rats
  • Receptor, Cannabinoid, CB1
  • Signal Transduction

Substances

  • Cannabinoids
  • Photosensitizing Agents
  • Receptor, Cannabinoid, CB1
  • Dronabinol