Kappa-agonists for the treatment of MS

New κ(kappa)-opioid receptor agonists for MS therapy. The pharmacokinetics will be controlled by the N-R group (red).
© Wünsch

Project title: Effects of newly generated, peripherally-selective, anti-inflammatory kappa-opioid receptor agonists in the treatment of progressive CNS inflammation and neurodegeneration
Principal investigators: Karin Loser, Bernhard Wünsch, Sonja Ständer
Project time: 07/2016 - 10/2018
Project code: FF-2016-11

Multiple Sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system (CNS). Is a therapy, which is restricted to the periphery (i.e. to sites where pathogenic effector cells are developing), sufficient to down-regulate inflammation in the CNS? Which role might agonists of the κ(kappa) opioid receptor, a subtype of opioid receptors, play in this scenario? These are questions, which will be addressed by researchers from different disciplines in this CiM project.

The biologist Prof. Dr. Karin Loser, together with the medicinal chemist Prof. Dr. Bernhard Wünsch and the dermatologist Prof. Dr. Sonja Ständer are investigating how systemic inflammation and autoimmunity can be reduced. They already collaborated successfully during the development of a new, anti-inflammatory drug for the treatment of atopic dermatitis, which in a clinical trial has shown promising results in patients. Karin Loser and Sonja Ständer characterized the efficacy of newly generated κ agonists, which were developed by Bernhard Wünsch, in cell culture systems, animal models for atopic dermatitis, and in patient samples. The researchers are now following-up their approach and investigate whether similar κ agonists could also be used for the treatment of MS.

The activation of κ receptors by agonists results in the inhibition of certain signalling pathways. For instance, the activation of pathogenic effector T cells is down-regulated, which impairs their ability to migrate to the CNS. In MS, decreased numbers of effector cells in the CNS minimizes neuronal damage and thus, might improve the symptoms. Notably, the newly developed κ agonists already inhibit the activation of pathogenic effector cells at sites where they develop, namely in the lung, the skin or the peripheral lymph nodes, before they reach the CNS.

The reason for this potency is a completely new chemical structure of the κ agonists and a major advantage of these innovative, peripherally active κ agonists might be a reduced spectrum of side-effects.

In this CiM project, the team of Bernhard Wünsch is optimizing the pharmacokinetics of κ agonists by the synthesis of structurally modified analogues. Most importantly, the new agonists should not be able to pass the blood-brain barrier. Moreover, the metabolic stability should be improved by reducing the biotransformation in the liver.

Karin Loser is characterizing the effects of the new κ agonists in various mouse models for MS. Her group is concentrating on elucidating cellular and molecular mechanisms. For example, she is analysing the concentration of pro-inflammatory mediators as well as the numbers of pathogenic effector cells in the CNS, the lung, the skin and the peripheral immune organs.

Sonja Ständer’s group subsequently studies the effects of the new drugs directly in the CNS tissue on a histological level. She is also responsible for morphological analyses, including immunofluorescent staining.