Discovery paves the way to next-generation antihistamines

Doxepin antihistamine

Researchers in Japan have revealed why geometric variants of doxepin have markedly different efficacies, paving the way to next-generation antihistamines with fewer side effects.

Doxepin is an antihistaminic, antidepressant, and sleeping aid that has two geometric isomers ­– molecules with equal chemical formulas but different 3D arrangements.

While its Z-isomer is known to be more effective than its E-isomer, the precise nature of its binding to the histamine H1 receptor previously remained elusive.

To understand this process, a research team from Tokyo University of Science, Japan, first produced a customised yeast expression vector that was used to modify yeast cultures so that they produce H1R. After retrieving the membranes from these cells, they applied a solution containing commercial doxepin, producing H1R-doxepin complexes.

Following extraction and purification of these complexes, they removed any excess (unbound) doxepin. Finally, by denaturing the H1R receptors, they could free the bound doxepin molecules and measure their numbers in a high-performance liquid chromatography setup.

Using this protocol, the researchers could accurately quantify the amount of each isomer that was bound to the extracted receptors, which is directly tied to their relative binding affinity. They found that the affinity to H1R of the Z-isomer was over five times higher than that of the E-isomer.

Through experiments on a mutant variant of H1R coupled with molecular dynamics simulations, they revealed that the Thr112 side chain in the ligand-binding pocket of H1R creates a chemical environment that enhances selectivity for the Z-isomer.

“Our efforts could serve as the basis for designing next-generation antihistamines that are more effective and have fewer side effects,” said Professor Shiroishi. “Worth noting, this newfound knowledge will be useful for designing compounds that bind not only to H1R, but also other disease-relevant target proteins.”

Diana Spencer, Senior Digital Content Editor, DDW

Related Articles

Join FREE today and become a member
of Drug Discovery World

Membership includes:

  • Full access to the website including free and gated premium content in news, articles, business, regulatory, cancer research, intelligence and more.
  • Unlimited App access: current and archived digital issues of DDW magazine with search functionality, special in App only content and links to the latest industry news and information.
  • Weekly e-newsletter, a round-up of the most interesting and pertinent industry news and developments.
  • Whitepapers, eBooks and information from trusted third parties.
Join For Free