Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - SAFER (Selective Agonists For Serotonin Receptors)

Teaser

SAFER was established in 2017 with training and research activities initiated at the beginning of 2018 with the enrolment of five ESRs working towards the following scientific goals:1) Provide a rationale for the design of safer drugs by uncovering molecular mechanisms for...

Summary

SAFER was established in 2017 with training and research activities initiated at the beginning of 2018 with the enrolment of five ESRs working towards the following scientific goals:

1) Provide a rationale for the design of safer drugs by uncovering molecular mechanisms for functional selectivity at the serotonin 5-HT2A receptor.
2) Identify ligands with therapeutically favorable 5-HT2A signaling profile(s).
3) Develop a public GPCR ligand database including functionally selective agonists

Background:
Serotonin, or 5-hydroxytryptamine (5-HT), is a neurotransmitter that gives feelings of wellbeing and happiness, regulates mood, appetite, and sleep and also has cognitive functions, including memory and learning. The serotonergic system is very complex, comprising 14 different receptor subtypes: 13 G-protein-coupled receptors (GPCRs) and one ligand-gated ion channel. SAFER has a particular focus on the 5-HT2A receptor subtype, which is a validated drug target in the treatment of schizophrenia and other psychoses, cluster headaches and glaucoma. At UCPH, numerous agonists targeting this receptor have been developed including the most selective 5-HT2A receptor agonist reported to date, which is now being used to investigate the effects of selective activation of the 5-HT2A receptor in various animal models. Furthermore, at UCPH a PET-ligand ([11C]Cimbi-36) was taken “from bench to bedside” – i.e. from medicinal chemistry development to clinical applications.

Scientific problem:
There is accumulating clinical evidence that 5-HT2A receptor agonists can relieve the suffering of treatment-resistant depressive patients and anxiety in terminal cancer patients. However, their therapeutic mode of action is currently very poorly understood due to the unselective nature of the current drugs. Furthermore, the impact of selectively activating different signaling pathways of the 5-HT2A receptor is unknown, as such functionally selective ligands remains to be discovered.

SAFER solution:
Recent developments in GPCR pharmacology have shown that agonists can exhibit functional selectivity by preferentially triggering alternative intracellular signaling pathways. SAFER will exploit this mechanism to identify functionally Selective Agonists For the 5-HT2A Serotonin Receptor. Combining UCPH’s knowledge about the development of ligands for the 5-HT2A receptor, GPCR pharmacology, computational chemistry and database development with Enamine’s extensive know-how within chemistry and SAR’s structural biology profile, SAFER is ideally positioned to address this important scientific and societal challenge.

Impact:
SAFER will provide the first tools for dissection of 5-HT2A signaling and apply them to reveal the therapeutic mechanisms of 5-HT2A agonists. This will open up clinical opportunities beyond this 3-year program. As the most important part of this program SAFER will provide training for 5 ESRs as the next generation of researchers in this important field of health science.

Work performed

In the initial phase of the project, SAFER has focused on the identification of new lead molecules that is able to differentiate between the different pathways which the 5-HT2AR uses for cell-signaling. We have established and implemented the required pharmacological assays and screened an in-house library of 5-HT2AR agonists. From this screening, we have identified several leads that SAFER with investigating in further detail using various techniques – structural biology, computational chemistry/modeling, and medicinal chemistry optimization. Furthermore, we have established a platform for annotating and sharing literature data on biased agonists to make this readily available to the scientific community and the public in general.

Final results

SAFER will focus on identifying biased agonists that can be used investigate the structural requirements for biased agonism at the 5-HT2AR – using both computational and structural biology. We will strive to crystallize the 5-HT2AR using one of the constructs identified within SAFER with a selection of different SAFER-ligands. Furthermore, after the evaluation of the DMPK-profile, we will look to investigate the in vivo effects of biased agonists in various animal models.

Website & more info

More info: http://www.safer-itn.eu/.