Selective Neuropeptide Y Receptor Ligands

The C-terminal residues Arg33, Arg35 and Tyr36-NH2 of neuropeptide Y (NPY) are most crucial for binding to NPY receptors. Different argininamide-type mimics of the C-terminus of NPY were identified as high affinity NPY receptor ligands, e.g. the (R)-Arg derivative BIBP 3226, an Y1R antagonist, and the (S)-configured Arg derivative BIIE 0246, a potent Y2R antagonist. Both compounds are used as standard NPY receptor ligands. However, their in vivo application is limited due to the strongly basic guanidino group (pKa value about 13) which is incompatible with oral bioavailability. We found that the introduction of acyl substituents at the N(G)-position of BIBP 3226 results in analogues with comparable or increased Y1R antagonistic activity. The basicity of these derivatives is by 4-5 orders of magnitude lower than that of the parent compound, i. e. a considerable portion of the acylguanidines is uncharged at physiological pH. Moreover, such compounds are capable of penetrating into the CNS. The aim of this project is to further explore the aforementioned strategy by preparation of guanidine-derived NPY receptor antagonists with reduced basicity.

As some of the aforementioned N(G)-substituted argininamides had considerably higher receptor affinity than the parent compound we focused on the development of radio- (18F, 3H) and fluorescence-labelled Y1R antagonists starting from amino-functionalized building blocks. The labelled Y1R ligands will serve as pharmacological tools as well as in vitro and in vivo diagnostics.

Nonpeptidic NPY Y1, Y2 and Y4 receptor antagonists
Radio- and fluorescence-labelled NPY receptor ligands

Collaboration with Prof. Dr. A. Beck-Sickinger (Institute of Biochemistry, University of Leipzig), Prof. Dr. Chiara Cabrele (Organic Chemistry, University of Bochum), Prof. Dr. Burkhard König (Organic Chemistry, University of Regensburg), Prof. Dr. O. Reiser (Organic Chemistry, University of Regensburg).

Selected publications:

M. Keller, N. Pop, C. Hutzler, A. G. Beck-Sickinger, G. Bernhardt, A. Buschauer, Guanidine - acylguanidine bioisosteric approach in the design of radioligands: Synthesis of a tritium-labeled N(G)-propionylargininamide ([3H]-UR-MK114) as a highly potent and selective neuropeptide Y Y1 receptor antagonist. J. Med. Chem. 51 (24), 8168-8172 (2008)

S. Weiss, M. Keller, G. Bernhardt, A. Buschauer, B. König, Modular synthesis of non-peptidic bivalent NPY Y1 receptor antagonists. Bioorg. Med. Chem. 16, 9858–9866 (2008)
E. Schneider, M. Keller, A. Brennauer, B. K. Hoefelschweiger, D. Gross, O. S. Wolfbeis, G. Bernhardt, A. Buschauer, Synthesis and Characterization of the First Fluorescent Nonpeptide NPY Y1 Receptor Antagonist. ChemBioChem 8 (16), 1981-1988 (2007)
R. Ziemek, E. Schneider, A. Kraus, C. Cabrele, A.G. Beck-Sickinger, G. Bernhardt, A. Buschauer, Determination of affinity and activity of ligands at the human neuropeptide Y Y4 receptor by flow cytometry and aequorin luminescence. J. Recept. Signal Transduct. Res. 27 (4), 217-233 (2007)
R. Ziemek, A. Brennauer, E. Schneider, C. Cabrele, A.G. Beck-Sickinger, G. Bernhardt, A. Buschauer, Fluorescence- and luminescence-based methods for the determination of affinity and activity of neuropeptide Y(2) receptor ligands. Eur. J. Pharmacol. 551 (1-3), 10-18 (2006).
E. Schneider, M. Mayer, R. Ziemek, L. Li, C. Hutzler, G. Bernhardt, A. Buschauer, A Simple and Powerful Flow Cytometric Method for the Simultaneous Determination of Multiple Parameters at G-Protein-coupled Receptor Subtypes. ChemBioChem 7 (9), 1400-1409 (2006).
A. Brennauer, S. Dove, A. Buschauer, Structure-Activity Relationships of Nonpeptide Neuropeptide Y Receptor Antagonists, in: M. C. Michel (ed.), Neuropeptide Y and related peptides, Handbook of Exp. Pharmacology, vol. 162, chapter 18, Springer, Berlin, Heidelberg (2004), pp. 505-546.
I. Aiglstorfer, I. Hendrich, C. Moser, G. Bernhardt, S. Dove, A. Buschauer, Structure-Activity Relationships of Neuropeptide Y Y1 Receptor Antagonists Related to BIBP 3226, Bioorg. Med. Chem. Lett. 10, 1597-1600 (2000).
C. Moser, G. Bernhardt, J. Michel, H. Schwarz, A. Buschauer, Cloning and functional expression of the hNPY Y5 receptor in human endometrial cancer (HEC-1B) cells , Can J. Physiol. Pharmacol. 78, 134-142 (2000).
S. Dove, M. C. Michel, S. Knieps, A. Buschauer , Pharmacology and quantitative structure-activity relationships of imidazolylpropylguanidines with mepyramine-like substructures as non-peptide neuropeptide Y Y1 receptor antagonists, Can. J. Physiol. Pharmacol. 78, 108-115 (2000).