Photochemical Control of Drug Efficacy: A Comparison of Uncaging and Photoswitching Ifenprodil on NMDA Receptors

Ek Raj Thapaliya, Laetitia Mony, Roberto Sanchez, Benjamin Serraz, Pierre Paoletti, Graham C.R. Ellis-Davies

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Ifenprodil is an important negative allosteric modulator of the N-methyl-D-aspartate (NMDA) receptor. We have synthesized caged and photoswitchable derivatives of this small molecule drug. Caged ifenprodil was biologically inert before photolysis, and UV irradiation efficiently released the drug allowing selective inhibition of GluN2B-containing NMDA receptors. Azobenzene-modified ifenprodil, on the other hand, is inert in both its trans and cis configurations, although in silico modeling predicted the trans form to be able to bind to the receptor. The disparity in effectiveness between the two compounds reflects, in part, the inherent ability of each method in manipulating the binding properties of drugs. With appropriate structure-activity relationship uncaging enables binary control of effector binding, whereas photoswitching using freely diffusible chromophores shifts the dose-response curve of drug-receptor interaction. Our data suggest that the efficacy of pharmacophores having a confined binding site such as ifenprodil can be controlled more easily by uncaging in comparison to photoswitching.

Original languageEnglish
Pages (from-to)445-454
Number of pages10
JournalChemPhotoChem
Volume5
Issue number5
DOIs
StatePublished - May 2021

Keywords

  • NMDA
  • ifenprodil
  • photopharmacology
  • photoswitching
  • uncaging

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