KORATIN kappa-Opioid-Receptor Agonists for the Treatment of Inflammatory and Itching Skin Diseases
Final Report Abstract
Atopic eczema (AE) is one of the most common skin diseases in Europe. Clinically, it is characterized by extensive eczema, which is accompanied by severe, excruciating pruritus, which highly affects the quality of life. AE cannot be cured. The acute symptoms are usually treated with topical or systemic immunosuppressants, which are not suitable due to their side effects for long-term use. The κ-opioid receptor (κ) plays a pivotal role in the pathophysiology of AE and pruritus. Therefore, the development of new therapeutic options via topical κ agonists was the basic idea at the start of this project. We were able to design new and selective agonists, with a high specificity and affinity to the κ receptor combined with low affinity for the other opioid receptors (µ, δ receptors) and σ receptors. The most promising cis,trans-configured stereoisomers 17 were synthesized in an enantioselecitve manner. Several ligands of class 17 were carefully evaluated pharmacologically. Expression of κ and µ receptors in seven pruritic diseases (psoriasis, prurigo nodularis, mastocytosis, lichen planus AE, urticarial, cutaneous T-cell lymphoma) were investigated. κ receptors were mainly expressed in the keratinocytes in different pattern within the various diagnoses (basal, suprabasal, whole epidermis). Additionally κ receptors were also detected in fibroblasts, epidermal dendritic cells, sensory nerve and partially mast cells. Compared to normal skin we found a significant up-regulation of κ receptors in the skin of patients with AE and cutaneous T-cell lymphoma and a down-regulation in psoriatic skin. Dynorphins (Dyn A, Dyn B), the endogenous ligands of the κ-opioid receptor could also be detected in the epidermis and were found co-localized with the receptor. Interestingly, the expression of dynorphin does not appear to be linked directly to the expression of κ receptors in any disease. In patients with AE, we saw both a high regulation of the receptor and the ligand but in psoriasis dynorphin is up-regulated although the receptor is down-regulated. Our results suggest that the two receptors κ and µ are differently regulated. While the κ receptor is upregulated in AE and CTCL the expression level of the µ receptor seems unchanged relative to normal skin. In patients with mastocytosis and lichen planus is contrary vice versa. Here µ receptors are significantly upregulated (p <0.001). In an acute arachidonic acid-induced dermatitis model, as well as in an oxazolone-induced chronic contact allergy model we found a reduced inflammatory response and scratching behavior after treatment with the new κ agonists. To our knowledge, this is the first study that demonstrate efficacy of topically applied κ agonists on inflammatory and pruritic processes in the skin. Taken together, the newly developed κ agonists confirmed their efficacy for topical treatment of inflammatory and pruritic processes of the skin in animal models. Moreover, the most promising κ agonist ((R,S,S)-17a) was developed up to a phase Ib clinical study with AE patients. Thus, this project is an excellent example for the combination of research in academia and industry leading to both increase of basic knowledge and development of products for the market. The aim of science transfer from academia to industry was fully achieved with this project.
Publications
- Systemic kappa opioid receptor agonists in the treatment of chronic pruritus: a literature review. Acta Derm Venereol. 2012 Oct 10; 92(5):555-60
Phan NQ, Lotts T, Antal A, Bernhard JD, Ständer S
(See online at https://doi.org/10.2340/00015555-1353) - Bromolactamization: Key step in the stereoselective synthesis of enantiomerically pure, cis-configured perhydropyrroloquinoxalines. Chirality 2014, 26, 793 - 800
A. Schulte, X. Situ, S. Saito, B. Wünsch
(See online at https://doi.org/10.1002/chir.22350) - Combination of cyclohexane and piperazine based κ-opioid receptor agonists: Synthesis and pharmacological evaluation of trans,trans-configured perhydroquinoxalines. Bioorg. Med. Chem. 2014, 22, 3316 - 3324
C. Bourgeois, E. Werfel, D. Schepmann, B. Wünsch
(See online at https://doi.org/10.1016/j.bmc.2014.04.054) - Stereoselective synthesis of cis,cis-configured vicinal triamines. Eur. J. Org. Chem. 2014, 5749 - 5756
A. Schulte, S. Saito, B. Wünsch
(See online at https://doi.org/10.1002/ejoc.201402685) - Synthesis and pharmacological evaluation of 5-pyrrolidinylquinoxalines as a novel class of peripherally restricted κ-opioid receptor agonists. J. Med. Chem. 2014, 57, 6845 - 6860
C. Bourgeois, E. Werfel, F. Galla, K. Lehmkuhl, H. Torres-Gómez, D. Schepmann, B. Kögel, T. Christoph, W. Straßburger, W. Englberger, M. Soeberdt, S. Hüwel, H.-J. Galla, B. Wünsch
(See online at https://doi.org/10.1021/jm500940q) - Conformationally restricted κ-opioid receptor agonists: Synthesis and pharmacological evaluation of diastereoisomeric and enantiomeric decahydroquinoxalines. Bioorg Med Chem Lett. 2015 Nov 15;25(22):5326-30
Molenveld P, Bouzanne des Mazery R, Sterk GJ, Storcken RP, Autar R, van Oss B, van der Haas RN, Fröhlich R, Schepmann D, Wünsch B, Soeberdt M
(See online at https://doi.org/10.1016/j.bmcl.2015.09.040) - Effects of polar κ-receptor agonists designed for the periphery on ATP-induced Ca2+ release from keratinocytes. MedChemComm 2016, 7, 317-26
F. Galla, Ch. Bourgeois, K. Lehmkuhl, D. Schepmann, M. Soeberdt, T. Lotts, Ch. Abels, S. Ständer, B. Wünsch
(See online at https://doi.org/10.1039/c5md00414d) - Synthesis and pharmacological evaluation of conformationally restricted κ-opioid receptor agonists. Med. Chem. Commun., 2016,7, Issue 12, 2368-2380
Y. Wenker, M. Soeberdt, C. Daniliuc, S. Ständer, D. Schepmann, B. Wünsch
(See online at https://doi.org/10.1039/c6md00441e) - Topical nalfurafine exhibits anti-inflammatory and anti-pruritic effects in a murine model of AD. J Dermatol Sci December 2016, Volume 84, Issue 3, Pages 351–354
G.R. Elliott, R.A.P. Vanwersch, M. Soeberdt, D. Metze, T. Lotts, S. Ständer, C. Abels
(See online at https://doi.org/10.1016/j.jdermsci.2016.09.008)
