Conformational Restriction and Enantioseparation Increase Potency and Selectivity of Cyanoguanidine-Type Histamine H4 Receptor Agonists.

2-Cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[2-(phenylsulfanyl)ethyl]guanidine (UR-PI376, 1) is a potent and selective agonist of the human histamine H4 receptor (hH4R). To gain information on the active conformation, we synthesized analogues of 1 with a cyclopentane-1,3-diyl linker. Affinities and functional activities were determined at recombinant hHxR (x: 1-4) subtypes on Sf9 cell membranes (radioligand binding, [(35)S]GTPγS, or GTPase assays) and in part in luciferase assays on human or mouse H4R (HEK-293 cells). The most potent H4R agonists among 14 racemates were separated by chiral HPLC, yielding eight enantiomerically pure compounds. Configurations were assigned based on X-ray structures of intermediates and a stereocontrolled synthetic pathway. (+)-2-Cyano-1-{[trans-(1S,3S)-3-(1H-imidazol-4-yl)cyclopentyl]methyl}-3-[2-(phenylsulfanyl)ethyl]guanidine ((1S,3S)-UR-RG98, 39a) was the most potent H4R agonist in this series (EC50 11 nM; H4R vs H3R, >100-fold selectivity; H1R, H2R, negligible activities), whereas the optical antipode proved to be an H4R antagonist ([(35)S]GTPγS assay). MD simulations confirmed differential stabilization of the active and inactive H4R state by the enantiomers.

[1]  R. Seifert,et al.  Dimeric carbamoylguanidine-type histamine H2 receptor ligands: A new class of potent and selective agonists. , 2015, Bioorganic & medicinal chemistry.

[2]  H. Haas,et al.  International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors , 2015, Pharmacological Reviews.

[3]  Jennifer D. Venable,et al.  Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators. , 2015, Journal of medicinal chemistry.

[4]  A. Strasser,et al.  Molecular determinants for the high constitutive activity of the human histamine H4 receptor: functional studies on orthologues and mutants , 2015, British journal of pharmacology.

[5]  R. Seifert,et al.  No Evidence for Histamine H4 Receptor in Human Monocytes , 2014, The Journal of Pharmacology and Experimental Therapeutics.

[6]  R. Seifert,et al.  Histamine H4-receptor expression in the brain? , 2014, Naunyn-Schmiedeberg's Archives of Pharmacology.

[7]  R. Kiss,et al.  Novel histamine H4 receptor ligands and their potential therapeutic applications: an update , 2014, Expert opinion on therapeutic patents.

[8]  H. Stark,et al.  A search for functional histamine H4 receptors in the human, guinea pig and mouse brain , 2014, Naunyn-Schmiedeberg's Archives of Pharmacology.

[9]  Hans-Joachim Wittmann,et al.  Sodium binding to hH3R and hH4R — a molecular modeling study , 2014, Journal of Molecular Modeling.

[10]  Bin Chen,et al.  The Histamine H4 Receptor Antagonist, JNJ 39758979, Is Effective in Reducing Histamine-Induced Pruritus in a Randomized Clinical Study in Healthy Subjects , 2014, The Journal of Pharmacology and Experimental Therapeutics.

[11]  R. Thurmond,et al.  Clinical and Preclinical Characterization of the Histamine H4 Receptor Antagonist JNJ-39758979 , 2014, The Journal of Pharmacology and Experimental Therapeutics.

[12]  A. Buschauer,et al.  Synthesis and Functional Characterization of Imbutamine Analogs as Histamine H3 and H4 Receptor Ligands , 2014, Archiv der Pharmazie.

[13]  R. Thurmond,et al.  The histamine H4 receptor mediates inflammation and Th17 responses in preclinical models of arthritis , 2013, Annals of the rheumatic diseases.

[14]  H. Stark,et al.  Luciferase Reporter Gene Assay on Human, Murine and Rat Histamine H4 Receptor Orthologs: Correlations and Discrepancies between Distal and Proximal Readouts , 2013, PloS one.

[15]  Hans-Joachim Wittmann,et al.  Molecular modeling studies give hint for the existence of a symmetric hβ2R-Gαβγ-homodimer , 2013, Journal of Molecular Modeling.

[16]  R. Seifert,et al.  Incomplete activation of human eosinophils via the histamine H4-receptor: evidence for ligand-specific receptor conformations. , 2012, Biochemical pharmacology.

[17]  R. Stevens,et al.  Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions , 2012, Science.

[18]  A. Buschauer,et al.  Synthesis and Histamine H3 and H4 Receptor Activity of Conformationally Restricted Cyanoguanidines Related to UR‐PI376 , 2011, Archiv der Pharmazie.

[19]  C. Marson Targeting the histamine H4 receptor. , 2011, Chemical reviews.

[20]  S. Rasmussen,et al.  Crystal Structure of the β2Adrenergic Receptor-Gs protein complex , 2011, Nature.

[21]  Ruben Abagyan,et al.  Structure of the human histamine H1 receptor complex with doxepin , 2011, Nature.

[22]  A. Strasser,et al.  Paradoxical Stimulatory Effects of the “Standard” Histamine H4-Receptor Antagonist JNJ7777120: the H4 Receptor Joins the Club of 7 Transmembrane Domain Receptors Exhibiting Functional Selectivity , 2011, Molecular Pharmacology.

[23]  R. Seifert,et al.  Expression and functional properties of canine, rat, and murine histamine H4 receptors in Sf9 insect cells , 2011, Naunyn-Schmiedeberg's Archives of Pharmacology.

[24]  Patrick Igel,et al.  Histamine H4 receptor agonists. , 2010, Bioorganic & medicinal chemistry letters.

[25]  R. Seifert,et al.  Chiral NG-acylated hetarylpropylguanidine-type histamine H2 receptor agonists do not show significant stereoselectivity. , 2010, Bioorganic & medicinal chemistry letters.

[26]  Wen Jiang,et al.  Molecular Determinants of Ligand Binding to H4R Species Variants , 2010, Molecular Pharmacology.

[27]  R. Thurmond,et al.  The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation. , 2010, The Journal of investigative dermatology.

[28]  R. Seifert,et al.  Does the Histamine H4 Receptor Have a Pro- or Anti-Inflammatory Role in Murine Bronchial Asthma? , 2010, Pharmacology.

[29]  R. Seifert,et al.  No Evidence for Functional Selectivity of Proxyfan at the Human Histamine H3 Receptor Coupled to Defined Gi/Go Protein Heterotrimers , 2010, Journal of Pharmacology and Experimental Therapeutics.

[30]  A. Strasser,et al.  Synthesis and Structure−Activity Relationships of Cyanoguanidine-Type and Structurally Related Histamine H4 Receptor Agonists§ , 2009 .

[31]  R. Smits,et al.  Major advances in the development of histamine H4 receptor ligands. , 2009, Drug discovery today.

[32]  Krzysztof Palczewski,et al.  Conserved waters mediate structural and functional activation of family A (rhodopsin-like) G protein-coupled receptors , 2009, Proceedings of the National Academy of Sciences.

[33]  R. Seifert,et al.  N(G)-acylated imidazolylpropylguanidines as potent histamine H4 receptor agonists: selectivity by variation of the N(G)-substituent. , 2009, Journal of medicinal chemistry.

[34]  Roland Seifert,et al.  High constitutive activity and a G-protein-independent high-affinity state of the human histamine H(4)-receptor. , 2009, Biochemistry.

[35]  R. Seifert,et al.  Tritium‐Labeled N1‐[3‐(1H‐imidazol‐4‐yl)propyl]‐N2‐propionylguanidine ([3H]UR‐PI294), a High‐Affinity Histamine H3 and H4 Receptor Radioligand , 2009, ChemMedChem.

[36]  R. Seifert,et al.  Acylguanidines as bioisosteres of guanidines: NG-acylated imidazolylpropylguanidines, a new class of histamine H2 receptor agonists. , 2008, Journal of medicinal chemistry.

[37]  R. Smits,et al.  Discovery of S-(2-guanidylethyl)-isothiourea (VUF 8430) as a potent nonimidazole histamine H4 receptor agonist. , 2006, Journal of medicinal chemistry.

[38]  Jennifer D. Venable,et al.  The histamine H4 receptor in autoimmune disease , 2006, Expert opinion on investigational drugs.

[39]  S. Shuto,et al.  Stereochemical diversity-oriented conformational restriction strategy. Development of potent histamine H3 and/or H4 receptor antagonists with an imidazolylcyclopropane structure. , 2006, Journal of medicinal chemistry.

[40]  R. Smits,et al.  The emerging role of the histamine H4 receptor in anti-inflammatory therapy. , 2006, Current topics in medicinal chemistry.

[41]  R. Seifert,et al.  Probing Ligand-Specific Histamine H1- and H2-Receptor Conformations with NG-Acylated Imidazolylpropylguanidines , 2006, Journal of Pharmacology and Experimental Therapeutics.

[42]  R. Thurmond,et al.  The histamine H4 receptor as a new therapeutic target for inflammation. , 2005, Trends in pharmacological sciences.

[43]  Rob Leurs,et al.  Evaluation of Histamine H1-, H2-, and H3-Receptor Ligands at the Human Histamine H4 Receptor: Identification of 4-Methylhistamine as the First Potent and Selective H4 Receptor Agonist , 2005, Journal of Pharmacology and Experimental Therapeutics.

[44]  J. Mieloszynski,et al.  Ruthenium catalysed oxidation without CCl4 of oleic acid, other monoenic fatty acids and alkenes , 2005 .

[45]  A. W. Schüttelkopf,et al.  PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. , 2004, Acta crystallographica. Section D, Biological crystallography.

[46]  J. A. Jablonowski,et al.  The first potent and selective non-imidazole human histamine H4 receptor antagonists. , 2003, Journal of medicinal chemistry.

[47]  T. Bürckstümmer,et al.  Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H1-Receptor , 2003, Journal of Pharmacology and Experimental Therapeutics.

[48]  Rob Leurs,et al.  A selective human H(4)-receptor agonist: (-)-2-cyano-1-methyl-3-[(2R,5R)-5- [1H-imidazol-4(5)-yl]tetrahydrofuran-2-y] methylguanidine. , 2003, Journal of medicinal chemistry.

[49]  T. Bürckstümmer,et al.  The human histamine H2‐receptor couples more efficiently to Sf9 insect cell Gs‐proteins than to insect cell Gq‐proteins: limitations of Sf9 cells for the analysis of receptor/Gq‐protein coupling , 2002, Journal of neurochemistry.

[50]  J. Schwartz,et al.  Histamine H3‐receptor‐mediated [35S]GTPγ[S] binding: evidence for constitutive activity of the recombinant and native rat and human H3 receptors , 2002, British journal of pharmacology.

[51]  T. Bürckstümmer,et al.  Distinct interaction of human and guinea pig histamine H2-receptor with guanidine-type agonists. , 2001, Molecular pharmacology.

[52]  R. Seifert,et al.  Similar apparent constitutive activity of human histamine H(2)-receptor fused to long and short splice variants of G(salpha). , 2001, The Journal of pharmacology and experimental therapeutics.

[53]  T. Lovenberg,et al.  Comparison of human, mouse, rat, and guinea pig histamine H4 receptors reveals substantial pharmacological species variation. , 2001, The Journal of pharmacology and experimental therapeutics.

[54]  J. Boutin,et al.  Structure and expression of the human histamine H4-receptor gene. , 2001, Biochemical and biophysical research communications.

[55]  B. Kobilka,et al.  Functional differences between full and partial agonists: evidence for ligand-specific receptor conformations. , 2001, The Journal of pharmacology and experimental therapeutics.

[56]  V. Setola,et al.  Discovery of a novel member of the histamine receptor family. , 2001, Molecular pharmacology.

[57]  L B Hough,et al.  Genomics meets histamine receptors: new subtypes, new receptors. , 2001, Molecular pharmacology.

[58]  Nicholas J. Carruthers,et al.  Cloning and pharmacological characterization of a fourth histamine receptor (H(4)) expressed in bone marrow. , 2001, Molecular pharmacology.

[59]  C. M. Davenport,et al.  Cloning, expression, and pharmacological characterization of a novel human histamine receptor. , 2001, Molecular pharmacology.

[60]  F. Monsma,et al.  Cloning and characterization of a novel human histamine receptor. , 2001, The Journal of pharmacology and experimental therapeutics.

[61]  K. Tanaka,et al.  Molecular cloning and characterization of a new human histamine receptor, HH4R. , 2000, Biochemical and biophysical research communications.

[62]  Y. Masuho,et al.  Molecular Cloning and Characterization of a Novel Type of Histamine Receptor Preferentially Expressed in Leukocytes* , 2000, The Journal of Biological Chemistry.

[63]  A. Yamatodani,et al.  Synthesis of 4(5)-[5-(Aminomethyl)tetrahydrofuran-2-yl- or 5-(Aminomethyl)-2,5-dihydrofuran-2-yl]imidazoles by Efficient Use of a PhSe Group: Application to Novel Histamine H3-Ligands1 , 1999 .

[64]  A. Yamatodani,et al.  Synthesis of imifuramine and its stereoisomers exhibiting histamine H3-agonistic activity , 1999 .

[65]  S. Sprang,et al.  The structure of the G protein heterotrimer Giα1 β 1 γ 2 , 1995, Cell.

[66]  J. Lange,et al.  Two novel syntheses of the histamine H3 antagonist thioperamide , 1995 .

[67]  K. Jakobs,et al.  Muscarinic acetylcholine receptor-stimulated binding of guanosine 5'-O-(3-thiotriphosphate) to guanine-nucleotide-binding proteins in cardiac membranes. , 1989, European journal of biochemistry.

[68]  D. Davey,et al.  Convenient synthesis of 4-methylhistamine and racemic .alpha.,4-dimethylhistamine and .alpha.,4-dimethylhistidine , 1989 .

[69]  R. S. Hinks,et al.  Enzymes in organic synthesis. 33. Stereoselective pig liver esterase-catalyzed hydrolyses of meso cyclopentyl-, tetrahydrofuranyl-, and tetrahydrothiophenyl-1,3-diesters , 1985 .

[70]  C. W. Scott,et al.  Reconstitution of catecholamine-stimulated binding of guanosine 5'-O-(3-thiotriphosphate) to the stimulatory GTP-binding protein of adenylate cyclase. , 1984, Biochemistry.

[71]  R. Webb,et al.  Diphenyl cyanocarbonimidate. A versatile synthon for the construction of heterocyclic systems , 1982 .

[72]  T. Walseth,et al.  The enzymatic preparation of [α-32P]nucleoside triphosphates, cyclic [32P]AMP, and cyclic [32P]GMP☆ , 1979 .

[73]  Y. Cheng,et al.  Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. , 1973, Biochemical pharmacology.

[74]  C. Pak,et al.  Selective reductions. XIX. Rapid reaction of carboxylic acids with borane-tetrahydrofuran. Remarkably convenient procedure for the selective conversion of carboxylic acids to the corresponding alcohols in the presence of other functional groups , 1973 .

[75]  O. Mitsunobu,et al.  Preparation of Esters of Phosphoric Acid by the Reaction of Trivalent Phosphorus Compounds with Diethyl Azodicarboxylate in the Presence of Alcohols , 1967 .

[76]  C. Pontes,et al.  Is the H4 receptor a new drug target for allergies and asthma? , 2013, Frontiers in bioscience.

[77]  Hans-Joachim Wittmann,et al.  Species-dependent activities of G-protein-coupled receptor ligands: lessons from histamine receptor orthologs. , 2013, Trends in pharmacological sciences.

[78]  P. Bonaventure,et al.  The future antihistamines: histamine H3 and H4 receptor ligands. , 2010, Advances in experimental medicine and biology.

[79]  Erwin W. Gelfand,et al.  The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines , 2008, Nature Reviews Drug Discovery.

[80]  G. Büchi,et al.  A two-step synthesis of imidazoles from aldehydes via 4-tosyloxazolines , 1994 .

[81]  R. Chěnevert,et al.  Chemoenzymatic enantioselective synthesis of amidinomycin , 1994 .

[82]  R. Chěnevert,et al.  Enantioselective synthesis of (+) and (-)-cis-3-aminocyclo-pentanecarboxylic acids by enzymatic asymmetrization , 1992 .

[83]  W. Szarek,et al.  Synthesis of cyclopentane analogs of 1-(2′,3′-dideoxy-β-glycero-pentofuranosyl)pyrimidine nucleosides , 1988 .

[84]  D. Eggleston,et al.  Diphenyl cyancarbonimidate and dichlorodiphenoxymethane as synthons for the construction of heterocyclic systems of medicinal interest , 1987 .

[85]  D. Swern,et al.  Oxidation of alcohols by “activated” dimethyl sulfoxide. a preparative, steric and mechanistic study , 1978 .

[86]  S. Birch,et al.  502. The configurations of the isomeric forms of 1: 3-dimethylcyclopentane , 1953 .

[87]  R. Thurmond,et al.  Dovepress Open Access to Scientific and Medical Research Open Access Full Text Article Pharmacological Characterization of Oxime Agonists of the Histamine H 4 Receptor , 2022 .