Published on the 5th July 2017 by ANSTO Staff
ANSTO Human Health researchers have co-led an international team investigating new treatments for depression. This research, recently published in the European Journal of Medicinal Chemistry, by a large team co led by Dr Benjamin Fraser and Dr Paul Callaghan at ANSTO, and Prof Lynette Daws of The University of Texas Health Science Center at San Antonio (UTHSCSA), evaluated antidepressant-like properties of novel compounds in preclinical behavioural and pharmacological studies.
This study sets the stage for further exploration of new compounds that will help researchers to develop new treatments for depression; treatments with therapeutic outcomes that improve upon selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed antidepressants, which are ineffective in many patients.
The new compounds are analogues of decynium-22 (D-22), a compound that blocks transport of “mood controlling” chemicals, called neurotransmitters, into neurons. D-22 does so by blocking transporters distinct from those blocked by SSRIs.
Importantly, preclinical research by Prof. Daws’ group showed that D-22 has potential as an “adjunct” treatment for depression. “Adjunct” means that when D-22 is co administered with an SSRI, the combination enhances extracellular serotonin levels through greater inhibition of serotonin clearance, and produces greater antidepressant-like effects, than that achieved with the SSRI alone.
The problem with D-22 is that it blocks transport of “mood controlling” chemicals via at least four different transporters.
“To understand the mechanisms by which D-22 augments the antidepressant effects of SSRIs we need compounds that are specific for each of these transporters” said Fraser.
The new analogues of D-22 were developed in the Radioisotopes and Radiotracer laboratories at ANSTO and then sent to Prof Daws at UTHSCSA, where they were evaluated for their antidepressant-like activity and binding profile to receptors than can mediate unwanted side effects.
It is strongly suspected the ANSTO compounds inhibit this other mechanism, contributing to their antidepressant-like effects.
“Prescribing medication for patients suffering depression is a significant challenge, and picking the right treatment is often a guessing game. Our new compounds may not only help treat depression, but in the future we could develop a first-in-class tool to study these transporters in humans. This could help doctors tailor treatment for individuals, which would be an enormous benefit to patients as it can take months to conclude that an antidepressant is not working adequately,” said Fraser.
A large number of ANSTO, national and international researchers contributed to this project including Naomi Wyatt, Dr Anwen Krause-Heuer and Dr Maxine Roberts who synthesised and isolated the active compounds.
The large team also involved post-graduate students supervised by Prof Naresh Kumar from The University of New South Wales and Dr Nial Wheate from The University of Sydney.
The team from UTHSCSA, which is led by Prof. Daws, included Dr Rheaclare Fraser-Spears, a postdoctoral researcher, who undertook much of the pharmacological experiments, and Dr Wouter Koek who led the animal behaviour studies.
http://www.sciencedirect.com/science/article/pii/S0223523417304579