Peter Gmeiner

Friedrich-Alexander-University Erlangen-Nürnberg | FAU · Department of Chemistry and Pharmacy

The Frizzled family (FZD1–10) of G protein-coupled receptors regulates WNT signaling mediating proliferative input. Dysregulation of FZD7 and exaggerated WNT/β-catenin signaling is frequently observed in intestinal cancers. Therefore, it is attractive to develop therapeutics targeting FZD7 for cancer treatment. Structure-based virtual screening has...

Bitter taste receptors (TAS2Rs), a subfamily of G-protein coupled receptors (GPCRs) expressed orally and extraorally, elicit signaling in response to a large set of tastants. Among 25 functional TAS2Rs encoded in the human genome, TAS2R14 is the most promiscuous, and responds to hundreds of chemically diverse ligands. Here we present the cryo–elect...

The determination of ligand–receptor binding affinities plays a key role in the development process of pharmaceuticals. While the classical radiochemical binding assay uses radioligands, fluorescence-based binding assays require fluorescent probes. Usually, radio- and fluorescence-labeled ligands are dissimilar in terms of structure and bioactivity...

Background The orexin receptor (OXR) plays a role in drug addiction and is aberrantly expressed in colorectal tumors. Subtype-selective OXR PET ligands suitable for in vivo use have not yet been reported. This work reports the development of ¹⁸F-labeled OXR PET ligand candidates derived from the OXR antagonist suvorexant and the OX1R-selective anta...

The delta opioid receptor (δOR or DOR) is a G protein-coupled receptor (GPCR) showing a promising profile as a drug target for nociception and analgesia. Herein, we design and synthesize new fluorescent antagonist probes with high δOR selectivity that are ideally suited for single-molecule microscopy (SMM) applications in unmodified, untagged recep...

Isotonitazene belongs to a potent class of μ‐opioid receptor (μOR) ligands, known as nitazenes. The lack of knowledge surrounding this agonist and others in its class has sparked thorough re‐investigations. To aid in these investigations, the purportedly covalent yet underexplored nitazene BIT was biochemically re‐evaluated in this work, along with...

Background: The orexin receptor (OXR) plays a role in drug addiction and appears as a tumor marker in colon carcinoma. Subtype-selective OXR PET ligands have not yet been reported. The present work deals with the development of 18F-labeled OXR ligands dervived from selective OX1R antagonist JH112. Methods: Applying computational analysis, medicinal...

The epithelial sodium channel (ENaC) mediates Na ⁺ absorption in several epithelia. Its impaired function leads to severe disorders, like pseudohypoaldosteronism type 1 and respiratory distress. Interestingly, a small molecule ENaC activator, the peptidomimetic S3969, stimulates human but not mouse αβγ-ENaC (Lu et al. 2008, J Biol Chem). Our aim wa...

Bitter taste receptors (TAS2Rs), a subfamily of G-protein coupled receptors (GPCRs) expressed orally and extraorally, elicit signaling in response to a large set of ligands. Among the 25 functional TAS2Rs encoded in the human genome, TAS2R14 is the most promiscuous, and responds to hundreds of chemically diverse agonists. Here, we present the cryo–...

G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by stimulating guanine nucleotide exchange in the Gα subunit¹. To visualize this mechanism, we developed a time-resolved cryo-EM approach that examines the progression of ensembles of pre-steady-state intermediates of a GPCR–G-protein complex. By monitoring the transitions of th...

The epithelial sodium channel (ENaC) is essential for mediating sodium absorption in several epithelia. Its impaired function leads to severe disorders, including pseudohypoaldosteronism type 1 and respiratory distress. Therefore, pharmacological ENaC activators have potential therapeutic implications. Previously, a small molecule ENaC activator (S...

2‐adrenergic receptor (β2‐AR) agonists are used for the treatment of asthma and chronic obstructive pulmonary disease, but also play a role in other complex disorders including cancer, diabetes and heart diseases. As the cellular and molecular mechanisms in various cells and tissues of the β2‐AR remain vastly elusive, we developed tools for this in...

Converting known ligands into photoswitchable derivatives offers the opportunity to modulate compound structure with light and hence, biological activity. In doing so, these probes provide unique control when evaluating G‐protein‐coupled receptor (GPCR) mechanism and function. Further conversion of such compounds into covalent probes, known as phot...

The G protein-coupled serotonin receptor 5-HT 1A R mediates antinociception and may serve as a valuable target for the treatment of pain. Starting from a chemical library, ST171, a bitopic chemotype activating 5-HT 1A R was evolved. In vitro pharmacological investigations of ST171 revealed potent and selective G i activation (EC 50 = 0.3 nM), with...

The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has subo...

The high affinity dopamine D4 receptor ligand APH199 and derivatives thereof exhibit bias toward the Gi signaling pathway over β-arrestin recruitment compared to quinpirole. Based on APH199, two novel groups of D4 subtype selective ligands were designed and evaluated, in which the original benzyl phenylsemicarbazide substructure was replaced by eit...

Alcohol consumption is a widespread behaviour that may eventually result in the development of alcohol use disorder (AUD). Alcohol, however, is rarely consumed in pure form but in fruit- or corn-derived preparations, like beer. These preparations add other compounds to the consumption, which may critically modify alcohol intake and AUD risk. We inv...

Activation of the µ-opioid receptor (µOR) by food components could lead to reward effects or to the modulation of motor functions in the gastrointestinal tract. In an unbiased search for novel µOR agonists in food, a three-step virtual-screening process selected 22 promising candidates with potential to interact with the µOR. Radioligand binding st...

The hypothesis that sustained G protein-coupled receptor (GPCR) signaling from endosomes mediates pain is based on studies with endocytosis inhibitors and lipid-conjugated or nanoparticle-encapsulated antagonists targeted to endosomes. GPCR antagonists that reverse sustained endosomal signaling and nociception are needed. However, the criteria for...

By using active pharmaceutical ingredients (APIs) previously recovered from expired drugs, it is shown that Selectfluor can act as a reagent for operationally simple late‐stage fluorination and chlorination of electron‐rich arenes under mild reaction conditions. As shown in mechanistic experiments, aromatic fluorination thereby competes with chlori...

G‐protein‐coupled receptors (GPCRs) play important roles in physiological processes and are modulated by drugs that either activate or block signaling. Rational design of the pharmacological efficacy profiles of GPCR ligands could enable the development of more efficient drugs, but is challenging even if high‐resolution receptor structures are avai...

G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β1 and β2 adrenergic receptors (β1AR and β2AR) are identical. Here, to examine the e...

The modulatory interactions between neurotensin (NT) and the dopaminergic neurotransmitter system in the brain suggest that NT may be associated with the progression of Parkinson's disease (PD). NT exerts its neurophysiological effects by interactions with the human NT receptors type 1 (hNTS1) and 2 (hNTS2). Therefore, both receptor subtypes are pr...

G protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by stimulating the exchange of guanine nucleotide in the G alpha subunit. To visualize this mechanism, we developed a time-resolved cryo-EM approach that examines the progression of ensembles of pre-steady-state intermediates of a GPCR-G protein complex. Using variability analys...

G protein‐coupled receptors (GPCR) play important roles in physiological processes and are modulated by drugs that either activate or block signaling. Rational design of the pharmacological efficacy profiles of GPCR ligands could enable the development of more efficient drugs, but is challenging even if high‐resolution receptor structures are avail...

The bitter taste receptor TAS2R14 is a G protein-coupled receptor that is found on the tongue as well as in the human airway smooth muscle and other extraoral tissues. Because its activation causes bronchodilatation, TAS2R14 is a potential target for the treatment of asthma or chronic obstructive pulmonary disease. Structural variations of flufenam...

The M2 muscarinic receptor (M2R) is a prototypical G-protein-coupled receptor (GPCR) that serves as a model system for understanding GPCR regulation by both orthosteric and allosteric ligands. Here, we investigate the mechanisms governing M2R signaling versatility using cryo-electron microscopy (cryo-EM) and NMR spectroscopy, focusing on the physio...

Leveraging biased signaling of G protein-coupled receptors has been proposed as a promising strategy for the development of drugs with higher specificity. However, the consequences of selectively targeting G protein- or β-arrestin-mediated signaling on cellular functions are not comprehensively understood. In this study, we utilized phosphoproteomi...

The human GPCR family comprises circa 800 members, activated by hundreds of thousands of compounds. Bitter taste receptors, TAS2Rs, constitute a large and distinct subfamily, expressed orally and extra-orally and involved in physiological and pathological conditions. TAS2R14 is the most promiscuous member, with over 150 agonists and 3 antagonists k...

The bitter taste receptor TAS2R14 is a G protein-coupled receptor that is found on the tongue as well as in the human airway smooth muscle and other extraoral tissues. Because its activation causes bronchodilatation, TAS2R14 is a potential target for the treatment of asthma or chronic obstructive pulmonary disease. Structural variations of flufenam...

Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α2A-adrenergic receptor (α2AAR), seeking new α2AAR agonists chemotypes that lack the sedation conferred by known α2AAR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as l...

Photoswitchable ligands as biological tools provide an opportunity to explore the kinetics and dynamics of the clinically relevant μ‐opioid receptor. These ligands can potentially activate or deactivate the receptor when desired by using light. Spatial and temporal control of biological activity allows for application in a diverse range of biologic...

G protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants. Besides human senses like vision and olfaction, taste perception is mostly mediated by GPCRs. Hence, the bitter taste receptor family TAS2R comprises 25 distinct receptors and plays a key role in food acceptan...

GPR88 is an orphan class A G-protein-coupled receptor that is highly expressed in the striatum and regulates diverse brain and behavioral functions. Here we present cryo-EM structures of the human GPR88-Gi1 signaling complex with or without a synthetic agonist (1R, 2R)-2-PCCA. We show that (1R, 2R)-2-PCCA is an allosteric modulator binding to a her...

The μ‐opioid receptor (μOR) is the major target for opioid analgesics. Activation of μOR initiates signaling through G protein pathways as well as through β‐arrestin recruitment. μOR agonists that are biased towards G protein signaling pathways demonstrate diminished side effects. PZM21, discovered by computational docking, is a G protein biased μO...

The μ‐opioid receptor (μOR) is the major target for opioid analgesics. Activation of μOR initiates signaling through G protein pathways as well as through β‐arrestin recruitment. μOR agonists that are biased towards G protein signaling pathways demonstrate diminished side effects. PZM21, discovered by computational docking, is a G protein biased μO...

The μ-opioid receptor (μOR) is the major target for opioid analgesics. Activation of μOR initiates signaling through G protein pathways as well as through β-arrestin recruitment. μOR agonists that are biased towards G protein signaling pathways demonstrate diminished side effects. PZM21, discovered by computational docking, is a G protein biased μO...

The α 2A adrenergic receptor (α 2A AR) is a G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor that mediates important physiological functions in response to the endogenous neurotransmitters norepinephrine and epinephrine, as well as numerous chemically distinct drugs. However, the molecular mechanisms of drug actions re...

A broadly applicable synthesis of peptides incorporating mixed disulfides between cysteine and homocysteine and cysteamine was developed. The method was established using pharmacologically relevant G protein-coupled receptor (GPCR) ligands including the μ-receptor agonist Dmt-DALDA and extended to the orexin derivative Oxa(17-33) and NT(8-13), the...

Dopamine D2 receptor (D2R), a G‐protein‐coupled receptor (GPCR), plays critical roles in neural functions and represents the target for a wide variety of drugs used to treat neurological diseases. However, its fundamental physicochemical properties, such as dimerization and affinity to different lipid environments, remain unknown. Here, reconstitut...

The family of neuropeptide Y (NPY) receptors comprises four subtypes (Y1R, Y2R, Y4R, Y5R), which are addressed by at least three endogenous peptides, i.e., NPY, peptide YY, and pancreatic polypeptide (PP), the latter showing a preference for Y4R. A series of cyclic oligopeptidic Y4R ligands were prepared by applying a novel approach, i.e., N-termin...

Bivalent ligands are composed of two pharmacophores connected by a spacer of variable size. These ligands are able to simultaneously recognize two binding sites, for example in a G protein-coupled receptor heterodimer, resulting in enhanced binding affinity. Taking advantage of previously described heterobivalent dopamine-neurotensin receptor ligan...

The human dopamine receptors D2S and D3 belong to the group of G protein-coupled receptors (GPCRs) and are important drug targets. Structural analyses and development of new receptor subtype specific drugs have been impeded by low expression yields or receptor instability. Fusing the T4 lysozyme into the intracellular loop 3 improves crystallizatio...

3-(2-Amino-4-methylthiazol-5-yl)propyl-substituted carbamoylguanidines are potent, subtype-selective histamine H2 receptor (H2R) agonists, but their applicability as pharmacological tools to elucidate the largely unknown H2R functions in the central nervous system (CNS) is compromised by their concomitant high affinity toward dopamine D2-like recep...

Significance We custom synthesize a fluorescent ligand and use highly sensitive microscopy methods to show that receptors may be targeted to distinct sites of a cell. We provide microscopic images of the localization of β 1 ‐adrenergic receptors (β 1 -ARs) and β 2 ‐adrenergic receptors (β 2 ‐ARs), main drivers of the contractility of the heart, in...

Allosteric modulators provide therapeutic advantages over orthosteric drugs. A plethora of allosteric modulators have been identified for several GPCRs, particularly for muscarinic receptors (mAChRs). To study the molecular mechanisms governing allosteric modulation, we utilized a recently developed NMR system to investigate the conformational chan...

The development of functionally selective or biased ligands is a promising approach towards drugs with less side effects. Biased ligands for G protein-coupled receptors can selectively induce G protein activation or β-arrestin recruitment. The consequences of this selective action on cellular functions, however, are not fully understood. Here, we i...

Neurotensin is an endogenous neuropeptide that acts as a potent modulator of ventral tegmental area (VTA) neurotransmission. The present study was aimed at determining VTA cell population and neurotensin receptor subtype responsible for the initiation of amphetamine‐induced psychomotor activity and extracellular signal‐regulated kinases (ERK1/2) se...

The family of human muscarinic acetylcholine receptors (MRs) is characterized by a high sequence homology among the five subtypes (M1R-M5R), being the reason for a lack of subtype selective MR ligands. In continuation of our work on dualsteric dibenzodiazepinone-type M2R antagonists, a series of M2R ligands containing a dibenzodiazepinone pharmacop...

Dopamine D2 receptors (D2Rs) are major targets in the treatment of psychiatric and neurodegenerative diseases. As with many other G protein-coupled receptors (GPCRs), D2Rs interact within the cellular membrane, leading to a transient receptor homo- or heterodimerization. These interactions are known to alter ligand binding, signaling, and receptor...

The human dopamine receptors D2S and D3 belong to the group of G protein-coupled receptors (GPCRs) and are important drug targets. Structural analyses and development of new receptor subtype specific drugs have been impeded by low expression yields or receptor instability. Fusing the T4 lysozyme into the intracellular loop 3 improves crystallizatio...

Fluorescent ligands are versatile tools for the study of G protein-coupled receptors. Depending on the fluorophore, they can be used for a range of different applications, including fluorescence microscopy and bioluminescence or fluorescence resonance energy transfer (BRET or FRET) assays. Starting from phenylpiperazines and indanylamines, privileg...

Background The therapeutic effects of antipsychotic drugs (APDs) are mainly attributed to their postsynaptic inhibitory functions on the dopamine D2 receptor, which, however, cannot explain the delayed onset of full therapeutic efficacy. It was previously shown that APDs accumulate in presynaptic vesicles during chronic treatment and are released l...

Beta adrenergic receptors (βARs) mediate physiologic responses to the catecholamines epinephrine and norepinephrine released by the sympathetic nervous system. While the hormone epinephrine binds β1AR and β2AR with similar affinity, the smaller neurotransmitter norepinephrine is approximately tenfold selective for the β1AR. To understand the struct...

In this Article, the configuration of BU72 at the benzylic amine was mistakenly reported as (S). Re-fitting this stereocentre to (R) improved the fit of the observed density in the X-ray structure. The (S)-configuration was originally assigned on the basis of the expected stereochemistry from ref. 1. The origin of the inversion is unclear, but we p...

The 3,4-dichloro-N-(1-(dimethylamino)cyclohexyl)methyl benzamide scaffold was studied as a template for ¹⁸F-positron emission tomography (¹⁸F-PET) radiotracer development emphasizing sensitivity to changes in opioid receptor (OR) occupancy over high affinity. Agonist potency, binding affinity, and relevant pharmacological parameters of 15 candidate...

Significance Orexin receptors belong to the superfamily of G-protein–coupled receptors (GPCRs) which represent the largest class of drug targets in humans. Despite the recent progress in structural biology, the development of subtype-selective orexin receptor and GPCR ligands in general remains challenging, due to the high sequence similarity among...

Most drugs acting on G-protein-coupled receptors target the orthosteric binding pocket where the native hormone or neurotransmitter binds. There is much interest in finding allosteric ligands for these targets because they modulate physiologic signaling and promise to be more selective than orthosteric ligands. Here we describe a newly developed al...

Introduction The dopamine D4 receptor (D4R) has attracted considerable attention as potential target for the treatment of a broad range of central nervous system disorders. Although many efforts have been made to improve the performance of putative radioligand candidates, there is still a lack of D4R selective tracers suitable for in vivo PET imagi...

Targeted structural modifications have led to a novel type of buprenorphine‐derived opioid receptor ligand displaying an improved selectivity profile for the μ‐OR subtype. On this basis, it is shown that phenylazocarboxamides may serve as useful bioisosteric replacements for the widely occurring cinnamide units, without loss of OR binding affinity...

Proteinase-activated receptor 2 (PAR2) is a class A G protein-coupled receptor (GPCR) whose activation has been associated with inflammatory diseases and cancer, thus representing a valuable therapeutic target. Pathophysiological roles of PAR2 are often characterized using peptidic PAR2 agonists. Peptidic ligands are frequently unstable in vivo and...

Background The therapeutic effects of antipsychotic drugs (APDs) are mainly attributed to their post synaptic inhibitory functions on the dopamine D2 receptor, which however, cannot explain the delayed onset of full therapeutic efficacy. It was previously shown that APDs accumulate in presynaptic vesicles during chronic treatment and are released l...

The α2 adrenergic receptors (α2ARs) are G protein-coupled receptors (GPCRs) that respond to adrenaline and noradrenaline and couple to the Gi/o family of G proteins. α2ARs play important roles in regulating the sympathetic nervous system. Dexmedetomidine is a highly selective α2AR agonist used in post-operative patients as an anxiety-reducing, seda...

Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M2R affinities (pKi (radioligand competition binding): 9.10-9.59). Binding studies at M1 and M3-M5 receptors indi...