Peter Gmeiner

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Organization: Friedrich Alexander University , Germany

Department: Department of Chemistry and Pharmacy

Title: (PhD)

TOPICS

Organic Chemistry

Chemicals
References

Discovery of dopamine D4 receptor antagonists with planar chirality

Co-reporter:Fabrizio Sanna, Birgit Ortner, Harald Hübner, Stefan Löber, Nuska Tschammer, Peter Gmeiner

Bioorganic & Medicinal Chemistry 2013 Volume 21(Issue 7) pp:1680-1684

Publication Date(Web):1 April 2013

DOI:10.1016/j.bmc.2013.01.065

Impact of the Proline Residue on Ligand Binding of Neurotensin Receptor2 (NTS2)-Selective PeptidePeptoid Hybrids

Co-reporter:Dr. Cornelia Held;Dr. Harald Hübner;Ralf Kling;Dr. Yvonne A. Nagel;Dr. Helma Wennemers;Dr. Peter Gmeiner

ChemMedChem 2013 Volume 8( Issue 5) pp:772-778

Publication Date(Web):

DOI:10.1002/cmdc.201300054

Abstract

To investigate the binding mode and structure–activity relationships (SARs) of selective neurotensin receptor 2 (NTS2) ligands, novel peptide–peptoid hybrids that simulate the function of the endogenous ligand were developed. Starting from our recently described NTS2 ligands of type 1, structural variants of type 2 and the metabolically stable analogues 3 a,b were developed. Replacement of the proline unit by a collection of structural surrogates and evaluation of the respective molecular probes for NTS2 affinity and selectivity indicated similar SARs as described for NT(8–13) derivatives bound to the subtype NTS1. Peptide–peptoid hybrids 2 d, 3 a,b showed substantial NTS2 binding affinity (K_i=8.1–16 nM) and 2400–8600-fold selectivity over NTS1. The thiazolidine derivative 3 b showed metabolic stability over 32 h in a serum degradation assay. In an inositol phosphate accumulation assay, the neurotensin mimetics 3 a and 3 b displayed an inhibition of constitutive activity exceeding 1.7–2.0 times the activity of NT(8–13). The fluorinated derivative 3 a could afford attractive opportunities to detect NTS2 by ¹⁹F magnetic resonance imaging.

Development of a Metabolically Stable Neurotensin Receptor2 (NTS2) Ligand

Co-reporter:Cornelia Held;Manuel Plomer;Dr. Harald Hübner;Dr. Jasmin Meltretter;Dr. Monika Pischetsrieder ;Dr. Peter Gmeiner

ChemMedChem 2013 Volume 8( Issue 1) pp:75-81

Publication Date(Web):

DOI:10.1002/cmdc.201200376

Abstract

Subtype-selective neurotensin receptor 2 (NTS2) ligands can be used as molecular probes to investigate the physiological role of neurotensinergic systems and serve as lead compounds to initiate the development of drugs for the treatment of tonic pain. Starting from our recently described NTS2 ligand 1, structural variants of type 2 were synthesized to further improve binding affinity and selectivity to gain metabolic stability. The peptide–peptoid hybrid 2 b showed excellent NTS2 binding affinity (K_i=2.8 nM) and 22 000-fold selectivity over NTS1, as well as metabolic stability over 32 h in a serum degradation assay. Employing a MAPK-driven luciferase reporter gene assay and an IP accumulation assay, the neurotensin mimetic 2 b displayed respective inhibitions of constitutive activity exceeding 4.3- and 3.9-fold that of the inverse agonist activity of the endogenous ligand neurotensin.

Bivalent molecular probes for dopamine D2-like receptors

Co-reporter:Daniela Huber, Stefan Löber, Harald Hübner, Peter Gmeiner

Bioorganic & Medicinal Chemistry 2012 Volume 20(Issue 1) pp:455-466

Publication Date(Web):1 January 2012

DOI:10.1016/j.bmc.2011.10.063

Novel azulene derivatives for the treatment of erectile dysfunction

Co-reporter:Stefan Löber, Harald Hübner, Armin Buschauer, Fabrizio Sanna, Antonio Argiolas, Maria Rosaria Melis, Peter Gmeiner

Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 23) pp:7151-7154

Publication Date(Web):1 December 2012

DOI:10.1016/j.bmcl.2012.09.064

Based on the dopamine D4 receptor partial agonist FAUC 3019, a series of azulenylmethylpiperazines was synthesized and affinities for the monoaminergic GPCRs including dopamine, serotonin, histamine and α-adrenergic receptor subtypes were determined. Ligand efficacies of the most promising test compounds revealed the N,N-dimethylaminomethyl substituted azulene 11 to be the most potent D4 partial agonist (EC50 = 0.41 nM). This candidate was investigated for its ability to promote penile erection. Applying an in vivo animal model, test compound 11 turned out to stimulate penile erection in male rats with superior potency in low concentrations when compared to apomorphine.

Selective Agonists for Dopamine/Neurotensin Receptor Heterodimers

Co-reporter:Susanne Koschatzky ;Dr. Peter Gmeiner

ChemMedChem 2012 Volume 7( Issue 3) pp:509-514

Publication Date(Web):

DOI:10.1002/cmdc.201100499

Abstract

The neuromodulatory peptide neurotensin has been described to functionally interact with dopaminergic pathways of the human brain. We employed radioligand binding studies to investigate the physical interaction between co-expressed dopamine D_2L or D₃ and neurotensin NTS₁ or NTS₂ receptors. Substantial cross-inhibitory effects of both receptor subtypes NTS₁ and NTS₂ on the agonist binding of D_2L or D₃ were detected in the presence of neurotensin. To identify ligand-specific modulation and subtype-dependent differences, the novel dopamine receptor agonists 5 and 6 bearing the 7-OH-DPAT pharmacophore were synthesized. Exceptional ligand specificity was observed for D₃–NTS₂ co-expression, which gave a 20-fold decrease in affinity for biphenylcarboxamide 5 in the presence of neurotensin. Comparing the binding properties of dopaminergic compounds in the presence of neurotensin, dopamine receptor subtype-selective profiles of the cross-inhibitory effect of neurotensin were observed.

Highly Potent 5-Aminotetrahydropyrazolopyridines: Enantioselective Dopamine D3 Receptor Binding, Functional Selectivity, and Analysis of Receptor−Ligand Interactions

Co-reporter:Nuska Tschammer ; Jan Elsner ; Angela Goetz ; Katharina Ehrlich ; Stefan Schuster ; Miriam Ruberg ; Julia Kühhorn ; Dawn Thompson ; Jennifer Whistler ; Harald Hübner

Journal of Medicinal Chemistry 2011 Volume 54(Issue 7) pp:2477-2491

Publication Date(Web):March 9, 2011

DOI:10.1021/jm101639t

Heterocyclic dopamine surrogates of types 5 and 7 were synthesized and investigated for their dopaminergic properties. The enantiomerically pure biphenylcarboxamide (S)-5a displayed an outstanding Ki of 27 pM at the agonist-labeled D3 receptor and significant selectivity over the D2 subtype. Measurement of [35S]GTPγS incorporation in the presence of a coexpressed PTX-insensitive Gα0−1 subunit indicated highly efficient G-protein coupling. Comparison of ligand efficacy data from cAMP accumulation and [3H]thymidine incorporation experiments revealed that ligand biased signaling is exerted by the test compound (S)-5a. Starting from the D3 crystal structure, a combination of homology modeling and site directed mutagenesis gave valuable insights into the binding mode and the intermolecular origins of stereospecific receptor recognition. According to these data, the superior affinity of the eutomer 5a is caused by the favorable binding energy that results from interaction between the ligand’s central ammonium unit and the aspartate residue in position 3.32 of the receptor.

Discovery of Highly Potent and Neurotensin Receptor 2 Selective Neurotensin Mimetics

Co-reporter:Jürgen Einsiedel ; Cornelia Held ; Maud Hervet ; Manuel Plomer ; Nuska Tschammer ; Harald Hübner

Journal of Medicinal Chemistry 2011 Volume 54(Issue 8) pp:2915-2923

Publication Date(Web):March 29, 2011

DOI:10.1021/jm200006c

The neurotensin receptor subtype 2 (NTS2) is involved in the modulation of tonic pain sensitivity and psychiatric diseases and is, therefore, regarded as a highly attractive pharmacological target protein. Aiming to discover NTS2 selective ligands, we herein describe the identification of screening hits and the chemical synthesis of structural variants leading to the highly potent and NTS2 selective peptide−peptoid hybrids of type 3. The neurotensin mimetics 3a and 3e−g incorporating an N-(4-hydroxyphenethyl)glycine substructure exhibit single digit nanomolar affinity (Ki = 4.3−8.8 nM) and 1900−12000 fold selectivity over the neurotensin receptor subtype 1 (NTS1). According to functional experiments, the test compounds 3a and 3e−g displayed an inhibition of constitutive mitogen-activated protein kinase (MAPK) activity exceeding 2.6−4.6 times the inverse agonist activity of the endogenous ligand neurotensin.

Development of a Bivalent Dopamine D2 Receptor Agonist

Co-reporter:Julia Kühhorn ; Angela Götz ; Harald Hübner ; Dawn Thompson ; Jennifer Whistler

Journal of Medicinal Chemistry 2011 Volume 54(Issue 22) pp:7911-7919

Publication Date(Web):October 17, 2011

DOI:10.1021/jm2009919

Bivalent D2 agonists may function as useful molecular probes for the discovery of novel neurological therapeutics. On the basis of our recently developed bivalent dopamine D2 receptor antagonists of type 1, the bivalent agonist 2 was synthesized when a spacer built from 22 atoms was employed. Compared to the monovalent control compound 6 containing a capped spacer, the bis-aminoindane derivative 2 revealed substantial steepening of the competition curve, indicating a bivalent binding mode. Dimer-specific Hill slopes were not a result of varying functional properties because both the dopaminergic 2 and the monovalent control agent 6 proved to be D2 agonists substantially inhibiting cAMP accumulation and inducing D2 receptor internalization. Investigation of the heterobivalent ligands 8 and 9, containing an agonist and a phenylpiperazine-based antagonist pharmacophore, revealed moderate steepening of the displacement curves and antagonist to very weak partial agonist properties.

Bivalent Dopamine D2 Receptor Ligands: Synthesis and Binding Properties

Co-reporter:Julia Kühhorn ; Harald Hübner

Journal of Medicinal Chemistry 2011 Volume 54(Issue 13) pp:4896-4903

Publication Date(Web):May 22, 2011

DOI:10.1021/jm2004859

Dopamine D2 receptor homodimers might be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising target proteins for the discovery of atypical antipsychotics. A highly attractive approach to investigate and control GPCR dimerization may be provided by the exploration and characterization of bivalent ligands, which can act as molecular probes simultaneously binding two adjacent binding sites of a dimer. The synthesis of bivalent dopamine D2 receptor ligands of type 1 is presented, incorporating the privileged structure of 1,4-disubstituted aromatic piperidines/piperazines (1,4-DAPs) and triazolyl-linked spacer elements. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for bivalent ligands with particular spacer lengths and a comparative analysis with respective monovalent control ligands and unsymmetrically substituted analogues indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites.

Cross-Receptor Interactions between Dopamine D2L and Neurotensin NTS1 Receptors Modulate Binding Affinities of Dopaminergics

Co-reporter:Susanne Koschatzky, Nuska Tschammer, and Peter Gmeiner

ACS Chemical Neuroscience 2011 Volume 2(Issue 6) pp:308

Publication Date(Web):April 11, 2011

DOI:10.1021/cn200020y

Dopaminergic systems have been described to functionally interact with the neuromodulatory peptide neurotensin. Employing fluorescence detected coimmunoprecipitation and radioligand binding experiments, we herein demonstrate that coexpression of dopamine D2L receptor and the neurotensin receptor subtype NTS1 leads to physical interaction and the formation of heteromers in transfected human embryonic kidney 293 cells. In this in vitro system, a trans-inhibitory effect on the agonist binding affinity of D2 was observed in presence of neurotensin. To correlate between the functional properties of dopaminergic agents and the magnitude of neurotensin-induced modulation of D2L binding affinities in cells coexpressing D2L and NTS1, a structurally diverse set of dopamine receptor agonists, partial agonists, and antagonists was tested. Ligand specific profiles indicating substantial bias between ligand efficacy and transmodulation were discovered, suggesting a heteromerization-based functional selectivity. In the presence of neurotensin, the novel D2 agonist FAUC 326 displayed a 34-fold decrease of binding affinity in cells coexpressing D2L and NTS1.Keywords: binding affinity; coexpression; coimmunoprecipitation; dimer; Dopamine D2L receptor; G-protein coupled receptor; GPCR; heteromer; intramembrane receptor−receptor interaction; negative cooperativity; neurotensin receptor 1; NTS1

Bioisosteric Replacement Leading to Biologically Active [2.2]Paracyclophanes with Altered Binding Profiles for Aminergic G-Protein-Coupled Receptors

Co-reporter:Marika Skultety ; Harald Hübner ; Stefan Löber

Journal of Medicinal Chemistry 2010 Volume 53(Issue 19) pp:7219-7228

Publication Date(Web):September 14, 2010

DOI:10.1021/jm100899z

Exploring the chemical diversity space of GPCR ligands, we recently discovered [2.2]paracyclophanes as valuable atypical bioisosteres for secondary affinity and selectivity generating moieties. To find out if such an exchange also works for structural moieties that simulate the endogenous neurotransmitter, π1 or π2 or both systems π1 and π2 of three representative privileged structures of types 1, 2, and 3 were replaced by a [2.2]paracyclophane unit. Contributions of the respective functionalities to the binding affinities of a panel of relevant monoaminergic GPCRs were systematically examined. The study led to the paracyclophanylpiperazine 3a displaying excellent D3 affinity (Ki = 1.6 nM) and a strongly attenuated binding to D4, 5-HT1 and α1. Whereas functional experiments showed neutral D3 antagonist properties, mutagenesis studies indicated a binding mode that is similar to its lead compounds of type 3.

Novel Pyridylmethylamines as Highly Selective 5-HT1A Superagonists

Co-reporter:Stefan Bollinger ; Harald Hübner ; Frank W. Heinemann ; Karsten Meyer

Journal of Medicinal Chemistry 2010 Volume 53(Issue 19) pp:7167-7179

Publication Date(Web):September 22, 2010

DOI:10.1021/jm100835q

To further improve the maximal serotonergic efficacy and better understand the configurational requirements for 5-HT1A binding and activation, we generated and biologically investigated structural variants of the lead structure befiradol. For a bioisosteric replacement of the 3-chloro-4-fluoro moiety, a focused library of 63 compounds by solution phase parallel synthesis was developed. Target binding of our compound collection was investigated, and their affinities for 5-HT2, α1, and α2-adrenergic as well as D1−D4 dopamine receptors were compared. For particularly interesting test compounds, intrinsic activities at 5-HT1A were examined in vitro employing a GTPγS assay. The investigation guided us to highly selective 5HT1A superagonists. The benzothiophene-3-carboxamide 8bt revealed almost exclusive 5HT1A recognition with a Ki value of 2.7 nM and a maximal efficacy of 124%. To get insights into the bioactive conformation of our compound collection, we synthesized conformationally constrained bicyclic scaffolds when SAR data indicated a chair-type geometry and an equatorially dispositioned aminomethyl substituent for the 4,4-disubstituted piperidine moiety.

Engineering a GPCR−Ligand Pair That Simulates the Activation of D2L by Dopamine

Co-reporter:Nuska Tschammer, Miriam Dörfler, Harald Hübner and Peter Gmeiner

ACS Chemical Neuroscience 2010 Volume 1(Issue 1) pp:25

Publication Date(Web):September 24, 2009

DOI:10.1021/cn900001b

In the past decade, engineered G-protein-coupled receptors activated solely by synthetic ligands (RASSLs) have been implemented as a new means to study neurotransmission, which is controlled by G-protein-coupled receptors in vitro and in vivo. In this study, we report an engineered dopamine receptor D2L F3906.52W, which is the first identified RASSL for the dopamine receptor family. The mutant receptor is characterized by a disrupted ligand binding and complete loss of efficacy for the endogenous ligand, dopamine, which is putatively due to a sterically induced perturbation of H-bonding with conserved serine residues in TM5. Based on this model, we rationally developed an aminoindane-derived set of agonists. Because these agonists forgo analogous H-bonding functionalities, their binding energy does not depend on the respective interactions. Binding affinity and potency were optimized by ligand modifications bearing molecular appendages that obviously interact with a secondary recognition site provided by four hydrophobic residues in TM2 and TM3. Thus, the ferrocenyl carboxamide 5b (FAUC 185) was identified as a synthetic agonist that is able to stimulate the mutant receptor in a manner similar to that by which endogenous dopamine activates the D2L wild-type receptor. The engineered dopamine receptor D2L F3906.52W in combination with FAUC 185 (5b) provides a new tool to probe GPCR functions selectively in specific cell populations in vitro and in vivo. Keywords (keywords): aminoindane; Dopamine D2L receptor; engineered receptor; ferrocenyl carboxamide; G-protein-coupled receptor, GPCR; receptor activated solely by synthetic ligands, RASSL

Anhydrotetracycline–peptide conjugates as representatives for ligand-based transactivating systems

Co-reporter:Susanne Lochner, Juergen Einsiedel, Gesa Schaefer, Christian Berens, Wolfgang Hillen, Peter Gmeiner

Bioorganic & Medicinal Chemistry 2010 Volume 18(Issue 16) pp:6127-6133

Publication Date(Web):15 August 2010

DOI:10.1016/j.bmc.2010.06.061

Bioconjugates of anhydrotetracycline and minimal activation sequences (VP1, VP2) derived from the Herpes simplex virus protein VP16 were synthesized. Different ligation strategies were applied and the resulting molecules tested in HeLa cells expressing the reverse transactivator rtTA-S3 for activity. The data clearly demonstrate that the atc-peptide conjugates are able to penetrate the cell membrane. Furthermore, binding to and induction of rtTA-S3 were detected. Structure–activity relationships indicated that the biological activity of the atc-peptide strongly depends on the specific linker used. The N-terminally linked oxime derivative 10 proved excellent activity when the increase of luciferace activity indicated a transcriptional activation substantially exceeding the inducing properties of anhydrotetracycline.

Click-Chemistry-Derived TetracyclineAmino Acid Conjugates Exhibiting Exceptional Potency and Exclusive Recognition of the Reverse Tet Repressor

Co-reporter:Igor Usai Dr.;Marcus Krueger;Jürgen Einsiedel Dr.;Wolfgang Hillen Dr. Dr.

ChemBioChem 2010 Volume 11( Issue 5) pp:703-712

Publication Date(Web):

DOI:10.1002/cbic.200900710

Abstract

A click-chemistry-based synthesis of biologically active doxycycline–amino acid conjugates is described. Starting from 9-aminodoxycycline derivatives and complementary functionalized amino acids, ligation was accomplished by copper(I)-catalyzed azide–alkyne [3+2] cycloaddition (CuAAC). The final products were tested in a variety of TetR and revTetR systems, and the C-terminally linked phenylalanine conjugate 12 c exhibited high selectivity for revTetR over TetR. Besides the unique property of the specific effector 12 c to effectively differentiate TetR and its reverse phenotype, the test compound proved to be almost devoid of any antibacterial activity; this will be highly beneficial for future applications to control gene expression in bacterial systems.

1,1′-Disubstituted Ferrocenes as Molecular Hinges in Mono- and Bivalent Dopamine Receptor Ligands

Co-reporter:Daniela Huber ; Harald Hübner

Journal of Medicinal Chemistry 2009 Volume 52(Issue 21) pp:6860-6870

Publication Date(Web):October 6, 2009

DOI:10.1021/jm901120h

On the basis of previous work on dopaminergic partial agonists of type 1 and 2, disubstituted ferrocenes are presented as valuable arene bioisosteres. Because substituents at the distal cyclopentadienyl ring are able to adjust the relative disposition that is required for ligand binding, disubstituted ferrocenes can act as molecular hinges. Taking advantage of click chemistry, the regioselective construction and functionalization of the target molecules is reported. Thus triazole derived appendages were used for the fine-tuning of biological activity and for the attachment of linker units generating bivalent GPCR ligands. Receptor binding was evaluated by radioligand displacement experiments, revealing superaffinity with sub- to single-digit nanomolar Ki values for particular test compounds. As a neutral antagonist at the dopamine receptors D3 and D4 and a potent partial agonist at the D2 subtype (intrinsic activity = 57%, EC50 = 2.5 nM), the bifunctional ferrocene 10b revealed a novel and unique activity profile.

Dopamine D2, D3, and D4 Selective Phenylpiperazines as Molecular Probes To Explore the Origins of Subtype Specific Receptor Binding

Co-reporter:Katharina Ehrlich ; Angela Götz ; Stefan Bollinger ; Nuska Tschammer ; Laura Bettinetti ; Steffen Härterich ; Harald Hübner ; Harald Lanig

Journal of Medicinal Chemistry 2009 Volume 52(Issue 15) pp:4923-4935

Publication Date(Web):July 16, 2009

DOI:10.1021/jm900690y

Assembling phenylpiperazines with 7a-azaindole via different spacer elements, we developed subtype selective dopamine receptor ligands of types 1a,c, 2a, and 3a preferentially interacting with D4, D2, and D3, respectively. To complete this set, the methylthio analogues 2b and 3b exceeding the affinity of 2a and 3a by one order of magnitude and the structural intermediate 1b were synthesized. These chemically similar but biologically divergent target compounds served as molecular probes for radioligand displacement experiments, mutagenesis, and docking studies on homology models based on the recent crystal structure of the β2-adrenergic receptor. Specific interactions with the highly conserved amino acids Asp3.32 and His6.55 and less conserved residues at positions 2.61, 2.64, 3.28, and 3.29 were identified. Inclusion of a carefully modeled extracellular loop 2 displayed two nonconserved residues in EL2 that differently contribute to ligand binding. Obviously, subtype selectivity is caused by nonconserved but frequently mediated by conserved amino acids.

Parallel synthesis of potent dopaminergic N-phenyltriazole carboxamides applying a novel click chemistry based phenol linker

Co-reporter:Pilar Rodriguez Loaiza, Stefan Löber, Harald Hübner, Peter Gmeiner

Bioorganic & Medicinal Chemistry 2009 Volume 17(Issue 15) pp:5482-5487

Publication Date(Web):1 August 2009

DOI:10.1016/j.bmc.2009.06.041

Taking advantage of our click chemistry based methodology to construct novel SPOS (solid phase organic synthesis) resins, the triazolylmethyl linked catechol 6a was discovered, which is readily available via copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) of azidomethyl substituted polystyrene with O-propargylcatechol and can be applied for the parallel synthesis of N-phenyltriazole carboxamides. As a proof-of-concept, a ‘catch-and-release’ strategy could be successfully applied for a parallel synthesis of dopaminergic phenyltriazoles of type 2. A focused model library of 20 test compounds revealing three points of diversity was generated by a three-step SPOS approach. Product purification was performed employing a solid-supported carboxylic acid anhydride as a scavenger. GPCR-ligand binding screening revealed dopamine D3 receptor ligands with Ki values in the single digit nanomolar range.

Diarylpropane-1,3-dione Derivatives as TetR-Inducing Tetracycline Mimetics: Synthesis and Biological Investigations

Co-reporter:Christian Kormann Dr.;Irina Pimenta;Stefan Löber Dr.;Cornelius Wimmer;Harald Lanig Dr.;Timothy Clark Dr.;Wolfgang Hillen Dr. Dr.

ChemBioChem 2009 Volume 10( Issue 18) pp:2924-2933

Publication Date(Web):

DOI:10.1002/cbic.200900564

Abstract

Synthesis, biological investigations and molecular docking studies of nonantibiotic and nontetracyclic inducers that feature a minimal key motif of the natural lead tetracycline are presented. The diarylpropane-1,3-dione motif was identified as the minimal substructure responsible for TetR induction by tetracyclines. The first nontetracyclic surrogates of the natural tetracyclines displayed significant inducing effects for TetR(BD)S135L, whereby the chlorohydroxyphenyl-substituted β-diketone 31 displayed the highest activity. Interestingly, antibiotic activity could not be detected for 31. Homology modeling based on the X-ray structure of 7-chlorotetracycline bound to TetR indicated analogous binding modes for the natural inducer and the synthetic diarylpropane-1,3-dione derivatives.

Novel triazolopeptides: chirospecific synthesis and conformational studies of proline derived analogs

Co-reporter:Andreas Paul, Juergen Einsiedel, Reiner Waibel, Frank W. Heinemann, Karsten Meyer, Peter Gmeiner

Tetrahedron 2009 65(31) pp: 6156-6168

Publication Date(Web):

DOI:10.1016/j.tet.2009.05.045

The Azulene Framework as a Novel Arene Bioisostere: Design of Potent Dopamine D4 Receptor Ligands Inducing Penile Erection

Co-reporter:Stefan Löber Dr.;Nuska Tschammer Dr.;Harald Hübner Dr.;Maria Rosaria Melis Dr.;Antonio Argiolas Dr. Dr.

ChemMedChem 2009 Volume 4( Issue 3) pp:325-328

Publication Date(Web):

DOI:10.1002/cmdc.200800395

Novel D3 Selective Dopaminergics Incorporating Enyne Units as Nonaromatic Catechol Bioisosteres: Synthesis, Bioactivity, and Mutagenesis Studies

Co-reporter:Miriam Dörfler ; Nuska Tschammer ; Katharina Hamperl ; Harald Hübner

Journal of Medicinal Chemistry 2008 Volume 51(Issue 21) pp:6829-6838

Publication Date(Web):October 4, 2008

DOI:10.1021/jm800895v

Enynes of type 4 and 5 as long chain derivatives of the nonaromatic dopamine D3 receptor agonist 3 (FAUC 73) were prepared by exploiting chemoselective functionalization of the azido-substituted vinyl triflate 9. Radioligand binding studies indicated excellent D3 affinity and selectivity over related GPCRs for the terminal alkynes 4c (FAUC 460) and 5c. Biphasic displacement curves gave picomolar Ki values for the high affinity binding site of D3. According to mitogenesis experiments and bioluminescence based cAMP assays, the biphenylcarboxamide 4c and its click chemistry derived triazole analogue 5c behaved as strong partial agonists but relative ligand efficacy significantly depended on the type of functional assay. Site directed mutagenesis involving the mutants D3 D3.32E, and D3 F6.51W implied that ligand interactions with D3.32 and F6.51 are highly crucial, giving rise to analogous binding modes for dopamine, classical and enyne type agonists.

Recent advances in the search for D3- and D4-selective drugs: probes, models and candidates

Co-reporter:Stefan Löber, Harald Hübner, Nuska Tschammer, Peter Gmeiner

Trends in Pharmacological Sciences (March 2011) Volume 32(Issue 3) pp:148-157

Publication Date(Web):1 March 2011

DOI:10.1016/j.tips.2010.12.003

Dopamine D2-like receptors (including D2, D3 and D4) belong to the ‘rhodopsin-like’ family of G protein-coupled receptors (GPCRs), which represent the largest group of targets for bioactive molecules. Due to their high sequence similarity, the design of subtype-selective ligands requires rational and effective strategies. The general formula of 1,4-disubstituted aromatic piperidines and piperazines (1,4-DAPs) was extracted from classical dopaminergic drugs. The biological properties of this compound family are encoded by an aromatic head group that controls intrinsic activity, an amine moiety and a lipophilic appendage. D3- and D4-selective molecular probes and drug candidates were generated from the general formula of 1,4-DAP. Formal structural rearrangement led to investigational drugs beyond the 1,4-DAP structure. The very recent publication of the X-ray crystal structure of D3 should facilitate efficient discovery of unprecedented chemotypes. However, the development of D3-selective agonists, functionally selective ligands and the exploitation of homo- and heteromers remain challenging.