Receptor Selectivity Research Articles

Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder.

The development of highly potent and selective μ opioid receptor (MOR) modulators with favorable drug-like properties has always been a focus in the opioid domain. Our previous efforts led to the discovery of a lead compound designated as NAT, a potent centrally acting MOR modulator. However, the fact that NAT precipitated considerable withdrawal effects at higher doses largely impaired its further development. In the light of the concept of activity cliff and CNS multiparameter optimization algorithm, a nitrogen atom was incorporated into the thiophene ring of NAT, aiming to preserve desirable pharmacological activities and CNS permeability while alleviating withdrawal symptoms. Among all 16 new analogs, compound 6 (NTZ) exhibited improved opioid receptor selectivity, enhanced in vivo antagonistic effect, and overall fewer withdrawal symptoms compared to NAT. Further assessment of several key drug-like properties suggested a favorable ADMET profile of NTZ. Taken together, NTZ shows promise as a potential lead to treat opioid use disorder.

Phenol (bio)isosteres in drug design and development.

Due to their versatile properties, phenolic compounds are integral to various biologically active molecules, including many pharmaceuticals. However, their application in drug design is often hindered by issues such as poor oral bioavailability, rapid metabolism, and potential toxicity. This review explores the use of phenol bioisosteres-structurally similar compounds that can mimic the biological activity of phenols while potentially offering improved drug-like properties. We provide an extensive analysis of various phenol bioisosteres, including benzimidazolones, benzoxazolones, indoles, quinolinones, and pyridones, highlighting their impact on the pharmacokinetic and pharmacodynamic profiles of drugs. Case studies illustrate the successful application of these bioisosteres in enhancing metabolic stability, receptor selectivity, and overall therapeutic efficacy. Additionally, the review addresses the challenges associated with phenol bioisosterism, such as maintaining potency and avoiding undesirable side effects. By offering a detailed examination of current strategies and potential future directions, this review serves as a valuable resource for medicinal chemists seeking to optimize phenolic scaffolds in drug development. The insights provided herein aim to facilitate the design of more effective and safer therapeutic agents through strategic bioisosteric modifications.

The association between alpha-blockers in the treatment of BPH and heart failure: A nationwide population-based cohort study in South Korea.

This study aimed to determine whether there is an association between the use of α-blockers to treat benign prostatic hyperplasia (BPH) and the development of heart failure in elderly Asian patients. An Elderly Cohort Database of the National Health Insurance Service was used to select 22,540 patients with newly diagnosed BPH between January 1, 2008, and December 31, 2018. They were divided into two equal groups, one prescribed α-blockers and one not. They were followed up through December 31, 2019. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the occurrence of heart failure with α-blockers. In addition, α-blockers were categorized according to α1a receptor selectivity to estimate the hazard ratios for heart failure. Heart failure occurred in 283 patients in the non-user group and 74 patients in the α-blocker group, with an incidence rate of 553.4 in the non-user group and 516.8 in the α-blocker group per 100,000 person-years. Although α-blocker users had a higher hazard ratio for heart failure compared to the non-user group, this was not statistically significant (HR: α-blocker HR 1.14, 95% CI 0.87 - 1.491). Furthermore, when α-blockers were stratified by selectivity, the results were also not statistically significant (non-selective α-blocker HR 0.86, 95% CI 0.31 - 2.36). In this nationwide, population-based cohort study, treatment with α-blockers was not associated with the incidence of heart failure in patients with BPH.

Structural insights into the agonist selectivity of the adenosine A3 receptor

Adenosine receptors play pivotal roles in physiological processes. Adenosine A3 receptor (A3R), the most recently identified adenosine receptor, is expressed in various tissues, exhibiting important roles in neuron, heart, and immune cells, and is often overexpressed in tumors, highlighting the therapeutic potential of A3R-selective agents. Recently, we identified RNA-derived N6-methyladenosine (m6A) as an endogenous agonist for A3R, suggesting the relationship between RNA-derived modified adenosine and A3R. Despite extensive studies on the other adenosine receptors, the selectivity mechanism of A3R, especially for A3R-selective agonists such as m6A and namodenoson, remained elusive. Here, we identify tRNA-derived N6-isopentenyl adenosine (i6A) as an A3R-selective ligand via screening of modified nucleosides against the adenosine receptors. Like m6A, i6A is found in the human body and may be an endogenous A3R ligand. Our cryo-EM analyses elucidate the A3R-Gi complexes bound to adenosine, 5’-N-ethylcarboxamidoadenosine (NECA), m6A, i6A, and namodenoson at overall resolutions of 3.27 Å (adenosine), 2.86 Å (NECA), 3.19 Å (m6A), 3.28 Å (i6A), and 3.20 Å (namodenoson), suggesting the selectivity and activation mechanism of A3R. We further conduct structure-guided engineering of m6A-insensitive A3R, which may aid future research targeting m6A and A3R, providing a molecular basis for future drug discovery.

Progress in GABAA receptor agonists for insomnia disorder.

Insomnia is the most common sleep disorder in which an individual has trouble falling or staying asleep. Chronic sleep loss interferes with daily functioning and adversely affects health. The main clinical drugs for insomnia are the positive allosteric modulator of the GABA (gamma-aminobutyric acid) A receptors (GABAARs) at the benzodiazepine site with selectivity of the GABA-α1 receptor. They are divided into benzodiazepine drugs and non-benzodiazepine drugs. Most recently, the first partial positive allosteric modulator of GABAAR Dimdazenil was approved by National Medical Products Administration (NMPA) and launched in China. This review summarized the mechanism of actions of current clinical drugs for insomnia, and the clinical applications of these drugs, which may help to understand their involvement in insomnia, and to search for more selective and potent ligands to be used in the treatment of insomnia.

Pemafibrate for treating MASLD complicated by hypertriglyceridaemia: a multicentre, open-label, randomised controlled trial study protocol

IntroductionNon-alcoholic fatty liver disease, now known as metabolic dysfunction-associated steatotic liver disease (MASLD), is a phenotype of the metabolic syndrome in the liver and is clearly associated with metabolic abnormalities...

Determination of Binding Constants and Gas Phase Stabilities of Artificial Carbohydrate Receptor Complexes Using Electrospray Mass Spectrometry.

In recent years, binding studies to determine complex stabilities and selectivities of artificial carbohydrate receptors with glycosides have been mainly performed using 1H NMR, isothermal titration calorimetry (ITC), and other spectroscopic titration techniques. Native electrospray ionization (ESI) mass spectrometry is used only to verify the complex stoichiometries, although determination of dissociation constants is also possible. Herein, the binding of a 1,3,5-substituted 2,4,6-triethylbenzene-based receptor (CHR) to four alkyl-β-d-glucosides with varying alkyl side chain lengths (methyl (MGP), hexyl (HGP), octyl (OGP), and dodecyl (DGP)-β-d-glucosides), which was analyzed by ESI Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR-MS) under optimized spray conditions in both ion modes, is reported. The complexes of the receptor with different sugars could be detected in 1:1 and 2:1 stoichiometries. Dissociation constants calculated for the 1:1 complexes showed a stability trend depending on the length of the alkyl side chain of the sugar: CHR:DGP > CHR:OGP > CHR:HGP > CHR:MGP. Gas phase stabilities determined by CID-MS confirm this relative trend in binding affinities. These findings substantiate the validity and applicability of ESI-MS as a method for investigating noncovalent complex stabilities and thus support research in the field of molecular recognition of carbohydrates by artificial receptors.

Styrylchromones: Biological Activities and Structure-Activity Relationship.

Styrylchromones (SC) are a group of oxygen-containing heterocyclic compounds, which are characterized by the attachment of a styryl group to the chromone core. SC can be found in nature or can be chemically synthesized in the laboratory. As their presence in nature is scarce, the synthetic origin is the most common. Two types of SC are known: 2-styrylchromones and 3-styrylchromones. However, 2-styrylchromones are the most common, being more commonly found in nature and which chemical synthesis is more commonly described. A wide variety of SC has been described in the literature, with different substituents in different positions, the majority of which are distributed on the A- and/or B-rings. Over the years, several biological activities have been attributed to SC. This work presents a comprehensive review of the biological activities attributed to SC and their structure-activity relationship, based in a published literature search, since 1989. The following biological activities are thoroughly revised and discussed in this review: antioxidant, antiallergic, antiviral, antibacterial, antifungal, anti-inflammatory and antitumoral, affinity and selectivity for A3 adenosine receptors, neuroprotective, and α-glucosidase inhibition. In general, SC are composed by a promising scaffold with great potential for the development of new drugs.

Preclinical in vitro and in vivo evaluation of [11C]ORM-13070 as PET ligand for alpha-2C adrenergic receptor occupancy using PET imaging in non-human primates.

This paper describes the preclinical validation of the radioligand [11C]ORM-13070 and its tritiated analog for addressing selectivity and occupancy of the selective alpha-2C adrenergic receptor (α2CR) antagonist BAY 292 in the cynomolgus brain. BAY 292 is a novel drug candidate being developed for the treatment of obstructive sleep apnea (OSA) via binding to central α2CR. In vitro autoradiography studies with sections from non-diseased post-mortem human caudate revealed an excellent specific binding window (>80%) using [3H]ORM-13070. BAY 292 bound to the same binding site as [3H]ORM-13070 and generated a good specific binding signal, with greater selectivity for α2CR. In non-human primates in vivo, [11C]ORM-13070 demonstrated a reversible behavior, with uptake at baseline highest in striatum (putamen, caudate, ventral striatum, and pallidum) and low in the cerebellar cortex, consistent with the known distribution of the α2CR. A dose dependent increase in receptor occupancy after BAY 292 administration was observed, confirming BBB penetration and target engagement. The estimated EC50 for BAY 292 is 33.39 ± 11.91 ng/mL. This study aimed to demonstrate the suitability of [11C]ORM-13070 as a PET-radioligand for the study of α2CR in the non-human primate brain, and to pave the way for future clinical PET tracer studies with BAY 292.

The role of beta blockers in the treatment of cardiovascular diseases

Beta-blockers are used to treat various cardiovascular diseases, including hypertension and chronic heart failure. They act by suppressing the effects of catecholamines through various pathways and affect heart rate, strength, and renin release, providing antihypertensive and anti-ischemic effects. The individual effects of various drugs on clinical outcomes in this group were determined according to characteristics of the patient, underlying disease, and type of beta-blocker used. In recent years, beta-blockers have faced a serious obstacle when new guidelines on hypertension suggest their use as second-line therapy after angiotensin converting enzyme inhibitors, angiotensin receptor blockers and slow calcium channel blockers in the absence of clear indications. In fact, these recommendations were based on meta-analyses that showed that beta-blockers have fewer beneficial effects on overall mortality, cardiovascular events, and brain stroke. In addition, according to currently available data, the appointment of beta-blockers for diseases such as heart failure with preserved ejection fraction and stable coronary heart disease can cause more harm than good outcomes. Bisoprolol is a beta-blocker with the highest selectivity for beta1-adrenergic receptors, which determines the rare frequency of side effects that develop because of its use. This review presents current data on the use of beta-blockers for treating cardiovascular diseases, with an emphasis on the use of bisoprolol.

Development of an Intravenously Stable Disulfide-Rich Peptide for the Treatment of Chemotherapy-Induced Neuropathic Pain.

α-conotoxins (α-Ctxs), a class of disulfide-rich conopetides, are excellent drug leads due to their small size, high selectivity, and potency for specific membrane receptors and ion channels involved in pain transmission. However, their high susceptibility to proteolytic degradation limits their therapeutic potential. In this study, we designed and synthesized a series of conformationally stable analogues of α-Ctx Mr1.1[S4Dap] using various structural optimization strategies. The Mr1.1[S4Dap, C16Pen] analogue maintained potency at human α9α10 nicotinic acetylcholine receptors, with a half-maximal inhibitory concentration (IC50) of 4 nM. It exhibited over a 5-fold increase in serum stability compared to Mr1.1[S4Dap], without disrupting its overall conformation. Furthermore, intravenous application of Mr1.1[S4Dap, C16Pen] showed potent analgesic activity in oxaliplatin-induced cold allodynia, indicating a high potential for drug development. Overall, the results from this study provide valuable insights for optimizing the serum stability of disulfide-rich peptides in future therapeutic applications.

Synthesis of Tryptamine-Thiazolidin-4-one Derivatives and the Combined In Silico and In Vitro Evaluation of their Biological Activity and Cytotoxicity.

Tryptamine, a monoamine alkaloid with an indole ring structure, is derived from the decarboxylation of the amino acid tryptophan, which is present in fungi, plants, and animals. Tryptamine analogues hold significant therapeutic potential due to their broad pharmacological activities, including roles as neurotransmitters and potential therapeutic agents for various diseases. Structural modifications of tryptamine enhance receptor selectivity and metabolic stability, improving therapeutic efficacy. These modifications are crucial for optimizing pharmacokinetic and pharmacodynamic properties, making the analogues more effective and safer for clinical use. In this study, novel tryptamine-thiazolidin-4-one (YS1-12) derivatives were synthesized via a one-pot three-component condensation reaction. The synthesized compounds are characterized by different spectroscopy techniques such as FT-IR, 1H NMR, 13C NMR, and HR-NMS. The synthesized compounds were subjected to binary QSAR disease models for bioactivity prediction and a target prediction model for target analysis. Potential targets were identified, and physics-based molecular simulations were conducted. Additionally, MM/GBSA binding free energy analysis was performed to calculate the average binding free energies of YS1-12 compared to reference molecules. Our computational results indicated promising biological activities for these new compounds. To further investigate these activities, the compounds were tested in vitro using two different cancer cell lines: YKG-1 glioblastoma and SH-SY5Y neuroblastoma cells. The results confirmed the potential activities of these novel compounds. Notably, compounds YS4 and YS10 exhibited favorable activities compared to the control compounds 5-FU and Temozolomide. YS4 demonstrated an IC50 value of 20 nM against YKG-1 cells, while YS10 exhibited an IC50 value of 0.44 nM against SH-SY5Y cells.

Mineralocorticoid receptor antagonists and heart failure with preserved ejection fraction: current understanding and future prospects.

The mineralocorticoid receptor (MR), part of the steroid hormone receptor subfamily within nuclear hormone receptors, is found in the kidney and various non-epithelial tissues, including the heart and blood vessels. When improperly activated, it can contribute to heart failure processes such as cardiac hypertrophy, fibrosis, stiffening of arteries, inflammation, and oxidative stress. MR antagonists (MRAs) have shown clear clinical benefits in patients with heart failure with reduced ejection fraction (HFrEF). However, in cases of heart failure with preserved ejection fraction (HFpEF), there is considerable diversity due to its complex underlying mechanisms, resulting in conflicting findings regarding the effectiveness of MRAs in relevant studies. The concept of phenomapping presents an encouraging avenue for investigating different intervention targets and novel therapies for HFpEF. Post hoc analysis of the TOPCAT trial identified certain HFpEF phenotypes that responded favorably to spironolactone. Growing clinical and preclinical evidence suggests that non-steroidal MRAs, which exhibit greater receptor selectivity, stronger anti-fibrotic and anti-inflammatory properties, and fewer hormone-related side effects, may emerge as another promising treatment option for HFpEF alongside sodium-glucose co-transporter 2 (SGLT2) inhibitors. This review aims to outline the structural and functional characteristics of MR, discuss the physiological effects of its activation and inhibition, and delve into the potential for personalized MRA therapy based on the concept of HFpEF phenotype.

In vitro and in vivo study of butyrylfentanyl and 4-fluorobutyrylfentanyl in female and male mice: Role of the CRF1 receptor in cardiorespiratory impairment.

Fentanyl analogues have been implicated in many cases of intoxication and death with overdose worldwide. The aim of this study is to investigate the pharmaco-toxicology of two fentanyl analogues: butyrylfentanyl (BUF) and 4-fluorobutyrylfentanyl (4F-BUF). In vitro, we measured agonist opioid receptor efficacy, potency, and selectivity and ability to promote interaction of the μ receptor with G protein and β-arrestin 2. In vivo, we evaluated thermal antinociception, stimulated motor activity and cardiorespiratory changes in female and male CD-1 mice injected with BUF or 4F-BUF (0.1-6 mg·kg-1). Opioid receptor specificity was investigated using naloxone (6 mg·kg-1). We investigated the possible role of stress in increasing cardiorespiratory toxicity using the corticotropin-releasing factor 1 (CRF1) antagonist antalarmin (10 mg·kg-1). Agonists displayed the following rank of potency at μ receptors: fentanyl > 4F-BUF > BUF. Fentanyl and BUF behaved as partial agonists for the β-arrestin 2 pathway, whereas 4F-BUF did not promote β-arrestin 2 recruitment. In vivo, we revealed sex differences in motor and cardiorespiratory impairments but not antinociception induced by BUF and 4F-BUF. Antalarmin alone was effective in blocking respiratory impairment induced by BUF in both sexes but not 4F-BUF. The combination of naloxone and antalarmin significantly enhanced naloxone reversal of the cardiorespiratory impairments induced by BUF and 4F-BUF in mice. In this study, we have uncovered a novel mechanism by which synthetic opioids induce respiratory depression, shedding new light on the role of CRF1 receptors in cardiorespiratory impairments by μ agonists.

Effects of Ring Functionalization in Anthracene-Based Cyclophanes on the Binding Properties Toward Nucleotides and DNA.

Supramolecular recognition of nucleobases and short sequences is an emerging research field focusing on possible applications to treat many diseases. Controlling the affinity and selectivity of synthetic receptors to target desired nucleotides or short sequences is a highly challenging task. Herein, we elucidate the effect of substituents in the phenyl ring of the anthracene-benzene azacyclophane on the recognition of nucleoside triphosphates (NTPs) and double-stranded DNA. We show that introducing phenyl rings increases the affinity for NTPs 10-fold and implements groove and intercalation binding modes with double-stranded DNA. NMR studies and molecular modeling calculations support the ability of cyclophanes to encapsulate nucleobases as part of nucleotides.

Structure elucidation of a human melanocortin-4 receptor specific orthosteric nanobody agonist

The melanocortin receptor 4 (MC4R) belongs to the melanocortin receptor family of G-protein coupled receptors and is a key switch in the leptin-melanocortin molecular axis that controls hunger and satiety. Brain-produced hormones such as α-melanocyte-stimulating hormone (agonist) and agouti-related peptide (inverse agonist) regulate the molecular communication of the MC4R axis but are promiscuous for melanocortin receptor subtypes and induce a wide array of biological effects. Here, we use a chimeric construct of conformation-selective, nanobody-based binding domain (a ConfoBody Cb80) and active state-stabilized MC4R-β2AR hybrid for efficient de novo discovery of a sequence diverse panel of MC4R-specific, potent and full agonistic nanobodies. We solve the active state MC4R structure in complex with the full agonistic nanobody pN162 at 3.4 Å resolution. The structure shows a distinct interaction with pN162 binding deeply in the orthosteric pocket. MC4R peptide agonists, such as the marketed setmelanotide, lack receptor selectivity and show off-target effects. In contrast, the agonistic nanobody is highly specific and hence can be a more suitable agent for anti-obesity therapeutic intervention via MC4R.

Design and Optimization of Selectivity-Tunable Toll-like Receptor 7/8 Agonists as Novel Antibody-Drug Conjugate Payloads.

Toll-like receptors 7 and 8 are involved in modulating the adaptive and innate immune responses, and their activation has shown promise as a therapeutic strategy in the field of immuno-oncology. While systemic exposure to TLR7/8 agonists can result in poor tolerance, combination therapies and targeted delivery through antibody-drug conjugates (ADCs) can help mitigate adverse effects. Described herein is the identification of a novel and potent series of pyrazolopyrimidine-based TLR7/8 agonists with tunable receptor selectivity. Representative agonists from this series were successfully able to induce the production of various proinflammatory cytokines and chemokines from human peripheral blood mononuclear cells. Anti-HER2-25 and anti-HER2-26 ADCs made from this class of payloads demonstrated mechanism-based activation of TLR7/8 in a THP1/N87 coculture system.

A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site

Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hD3R:GαOβγ complex bound to the D3R selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs.

Structural basis for the ligand recognition and G protein subtype selectivity of kisspeptin receptor.

Kisspeptin receptor (KISS1R), belonging to the class A peptide-GPCR family, plays a key role in the regulation of reproductive physiology after stimulation by kisspeptin and is regarded as an attractive drug target for reproductive diseases. Here, we demonstrated that KISS1R can couple to the Gi/o pathway besides the well-known Gq/11 pathway. We further resolved the cryo-electron microscopy (cryo-EM) structure of KISS1R-Gq and KISS1R-Gi complexes bound to the synthetic agonist TAK448 and structure of KISS1R-Gq complex bound to the endogenous agonist KP54. The high-resolution structures provided clear insights into mechanism of KISS1R recognition by its ligand and can facilitate the design of targeted drugs with high affinity to improve treatment effects. Moreover, the structural and functional analyses indicated that conformational differences in the extracellular loops (ECLs), intracellular loops (ICLs) of the receptor, and the "wavy hook" of the Gα subunit may account for the specificity of G protein coupling for KISS1R signaling.

Combining mutation and recombination statistics to infer clonal families in antibody repertoires.

B-cell repertoires are characterized by a diverse set of receptors of distinct specificities generated through two processes of somatic diversification: V(D)J recombination and somatic hypermutations. B-cell clonal families stem from the same V(D)J recombination event, but differ in their hypermutations. Clonal families identification is key to understanding B-cell repertoire function, evolution, and dynamics. We present HILARy (high-precision inference of lineages in antibody repertoires), an efficient, fast, and precise method to identify clonal families from single- or paired-chain repertoire sequencing datasets. HILARy combines probabilistic models that capture the receptor generation and selection statistics with adapted clustering methods to achieve consistently high inference accuracy. It automatically leverages the phylogenetic signal of shared mutations in difficult repertoire subsets. Exploiting the high sensitivity of the method, we find the statistics of evolutionary properties such as the site frequency spectrum and dN/dS ratio do not depend on the junction length. We also identify a broad range of selection pressures spanning two orders of magnitude.