Selective Histamine Receptor Ligands - Universität Regensburg

Arpromidine and related imidazolylpropylguanidines developed in our laboratory are the highly potent histamine H2 receptor (H2R) agonists. N(G)-acylated analogs of such guanidines turned out to be a promising new class of H2R agonists with improved pharmacokinetic properties due to substantially (by 4-5 orders of magnitude) reduced basicity compared to the corresponding N(G)-alkylated guanidines. In vivo studies confirmed that the reduced basicity results in absorption from the gastrointestinal tract and penetration across the blood brain barrier.
As imidazolylalkylguanidines show also more or less pronounced activities at H1R and in particular H3R and H4R, a lot of effort was dedicated to improving selectivity by bioisosteric approaches. The bioisosteric replacement of the imidazole with an aminothiazole resulted in highly potent and selective H2R agonists. Moreover, according to the “bivalent ligand approach”, histamine H2R agonists with two pharmacophoric moieties and various spacer lengths were synthesized to study the structure-activity relationship and to develop pharmacological tools for the investigation of hypothetical histamine receptors dimers. These bivalent acylguanidines turned out to be the most potent H2R agonists described so far with up to 4000-fold higher potency than histamine at the guinea pig right atrium and in GTPase assays with human (h) and guinea pig (gp) H2R-Gs(alpha)S fusion proteins expressed in Sf9 insect cells, respectively.

The human histamine H4 receptor (hH4R) seems to play a role in inflammatory and immunological processes, for example in eosinophil and mast cell chemotaxis. Selective agonists and antagonists are required for the characterisation of the H4R and the more detailed investigation of its (patho-) physiological role. Moreover, hH4R ligands are of potential value for the treatment of promyelocytic leukemia (agonists) or allergic and inflammatory diseases (antagonists). Previously, as part of a project to develop new histamine H2R agonists we synthesized a series of N(G)-acylated imidazolylpropylguanidines. Surprisingly, some of these acylguanidines turned out to be highly potent hH4R agonists with nanomolar activities in the GTPase assay. This unexpected result prompted us to further explore the H4R activities of acylguanidines and structurally related compounds. [3H]UR-PI294) was developed as a high-affinity radioligand for H3R and H4R. Attempts increase the H4R selectivity resulted in cyanoguanidines such as UR-PI376, which is among the most potent and selective H4R agonists known so far.

As part of a program to develop fluorescence-based methods for the study of ligand receptor interactions at G-protein coupled receptors (GPCRs) we have recently demonstrated that the affinity of agonists and antagonists can be determined by flow cytometry under equilibrium conditions by using cyanine5-labeled neuropeptide Y. This approach is very promising in case of peptides, and it could generally be a very attractive alternative to radioligand binding if it were also applicable to the investigation of small molecules acting at GPCRs such as biogenic amines and their antagonists. Therefore, suitable fluorescent probes are needed to investigate the applicability of such methods. Starting from roxatidine-like and mepyramine-like building blocks we prepared fluorescent H2 and H1 receptor antagonists with affinities in the range of therapeutically used drugs. With respect to reduction of background fluorescence the development of fluorescent probes emitting at wavelengths >650 nm is subject of ongoing work.

Histamine H2 receptor agonists
Histamine H4 receptor agonists
Fluorescent histamine receptor ligands

Collaboration with Prof. Elz (Pharm./Med. Chem. I) und Prof. Seifert (Dept. Pharmacology, Medical School of Hannover)

Selected publications:

P. Ghorai, A. Kraus, T. Birnkammer, R. Geyer, G. Bernhardt, S. Dove, R. Seifert, S. Elz, A. Buschauer, Chiral N(G)-acylated hetarylpropylguanidine-type histamine H2 receptor agonists do not show significant stereoselectivity. Bioorg. Med. Chem. Lett. 20 (10), 3173–3176 (2010)

P. Igel, R. Geyer, A. Strasser, S. Dove, R. Seifert, A. Buschauer, Synthesis and structure-activity relationships of cyanoguanidine-type and structurally related histamine H4 receptor agonists. J. Med. Chem. 52 (20), 6297–6313 (2009)

P. Igel, E. Schneider, D. Schnell, S. Elz, R. Seifert, A. Buschauer, N(G)-Acylated imidazolylpropylguanidines as potent histamine H4 receptor agonists: selectivity by variation of the N(G)-substituent. J. Med. Chem. 52 (8), 2623–2627 (2009)

P. Igel, D. Schnell, G. Bernhardt, R. Seifert, A. Buschauer, Tritium-labeled N1-[3-(1H-imidazol-4-yl)propyl]-N2-propionylguanidine ([3H]UR-PI294), a novel high affinity histamine H3 and H4 receptor radioligand. ChemMedChem 4 (2), 225-231 (2009)

A. Kraus, P. Ghorai, T. Birnkammer, D. Schnell, S. Elz, R. Seifert, S. Dove, G. Bernhardt, A. Buschauer, N(G)-Acylated aminothiazolylpropylguanidines as potent and selective histamine H2 receptor agonists, ChemMedChem, 4 (2), 232-240 (2009)

P. Ghorai, A. Kraus, M. Keller, C. Götte, P. Igel, E. Schneider, D. Schnell, G. Bernhardt, S. Dove, M. Zabel, S. Elz, R. Seifert, A. Buschauer, Acylguanidines as bioisosteres of guanidines: N(G)-acylated imidazolylpropylguanidines, a new class of histamine H2 receptor agonists. J. Med. Chem. 51 (22), 7193–7204 (2008)

H. Preuss, P. Ghorai, A. Kraus, S. Dove, A. Buschauer, R. Seifert, Mutations of Cys-17 and Ala-271 in the human histamine H2 receptor determine the species-selectivity of guanidine-type agonists and increase constitutive activity. J. Pharmacol. Exp. Ther. 321 (3), 975-982 (2007).

H. Preuss, P. Ghorai, A. Kraus, S. Dove, A. Buschauer, R. Seifert, Constitutive activity and ligand selectivity of human, guinea pig, rat, and canine histamine H2 receptors. J. Pharmacol. Exp. Ther. 321 (3), 983-995 (2007).

S.-X. Xie, F. Schalkhausser, Q.-Z. Ye, R. Seifert, A. Buschauer, Effects of impromidine- and arpromidine-derived guanidines on recombinant human and guinea pig histamine H(1)and H(2)receptors. Arch. Pharm. (Weinheim) 340 (1), 9-16 (2007).

S.-X. Xie, G. Petrache, E. Schneider, Q.-Z. Ye, G. Bernhardt, R. Seifert, A. Buschauer, Synthesis and pharmacological characterization of novel fluorescent histamine H2-receptor ligands derived from aminopotentidine. Bioorg. Med. Chem. Lett. 16 (15), 3886-3890 (2006).

S.-X. Xie, P. Ghorai, Q.-Z.Ye, A. Buschauer, R. Seifert, Probing Ligand-Specific Histamine H1- and H2-Receptor Conformations with NG-Acylated Imidazolylpropylguanidines. J. Pharmacol. Exp. Ther. 317 (1), 139-146 (2006).

S. Dove, S. Elz, R. Seifert, A. Buschauer, Structure-Activity Relationships of Histamine H2 Receptor Ligands, Mini-Rev. Med. Chem. 4, 941-954 (2004).

L. Li, J. Kracht, S. Peng, G. Bernhardt, S. Elz, A. Buschauer, Synthesis and pharmacological activity of fluorescent histamine H2 receptor antagonists related to potentidine, Bioorg. Med. Chem. Lett. 13, 1717-1720 (2003).

L. Li, J. Kracht, S. Peng, G. Bernhardt , A. Buschauer, Synthesis and pharmacological activity of fluorescent histamine H1 receptor antagonists related to mepyramine, Bioorg. Med. Chem. Lett. 13, 1245 - 1248 (2003).

M. T. Kelley, T. Bürckstümmer, K. Wenzel-Seifert, S. Dove, A. Buschauer, R. Seifert, Distinct interaction of human and guinea pig histamine H2-Receptor with guanidine-type agonists, Mol. Pharmacol. 60, 1210-1225 (2001).