IUPHAR Research Articles

The affinity-efficacy problem: an essential part of pharmacology education.

A fundamental mistake in receptor theory has led to an enduring misunderstanding of how to estimate the affinity and efficacy of an agonist. These properties are inextricably linked and cannot be easily separated in any case where the binding of a ligand induces a conformation change in its receptor. Consequently, binding curves and concentration-response relationships for receptor agonists have no straightforward interpretation. This problem-the affinity-efficacy problem-remains overlooked and misunderstood despite it being recognized in 1987. To avoid the further propagation of this misunderstanding, we propose in this review that the affinity-efficacy problem should be included in the core curricula for pharmacology undergraduates proposed by the British Pharmacological Society and the International Union of Basic and Clinical Pharmacology (IUPHAR).

Development of a pharmaceutical database as an aid to the nonclinical detection of drug-induced cardiac toxicity

The Health and Environmental Sciences Institute (HESI) Cardiac Safety Committee designed and created a publicly accessible database with an initial set of 128 pharmacologically defined pharmaceutical agents, many with known cardiotoxic properties. The database includes specific information about each compound that could be useful in evaluating hypotheses around mechanisms of drug-induced cardiac toxicity or for development of novel cardiovascular safety assays. Data on each of the compounds was obtained from published literature and online sources (e.g., DrugBank.ca and International Union of Basic and Clinical Pharmacology (IUPHAR) / British Pharmacological Society (BPS) Guide to PHARMACOLOGY) and was curated by 10 subject matter experts. The database includes information such as compound name, pharmacological mode of action, characterized cardiac mode of action, type of cardiac toxicity, known clinical cardiac toxicity profile, animal models used to evaluate the cardiotoxicity profile, routes of administration, and toxicokinetic parameters (i.e., Cmax). Data from both nonclinical and clinical studies are included for each compound. The user-friendly web interface allows for multiple approaches to search the database and is also intended to provide a means for the submission of new data/compounds from relevant users. This will ensure that the database is constantly updated and remains current. Such a data repository will not only aid the HESI working groups in defining drugs for use in any future studies, but safety scientists can also use the database as a vehicle of support for broader cardiovascular safety studies or exploring mechanisms of toxicity associated with certain pharmacological modes of action.

Addressing the gaps in evaluation of new drugs for older adults: Strategies from the International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee.

The International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee aims to improve the use of drugs in older adults and develop new therapeutic approaches for the syndromes and diseases of old age through advocacy, education, and research. In the present paper, we propose strategies relevant to drug development and evaluation, spanning preclinical and the full range of clinical studies. Drugs for older adults need to consider not only age, but also other characteristics common in geriatric patients, such as multimorbidity, polypharmacy, falls, cognitive impairment, and frailty. The IUPHAR Geriatric Committee's position statement on 'Measurement of Frailty in Drug Development and Evaluation' is included, highlighting 12 key principles that cover the spectrum of translational research. We propose that where older adults are likely to be major users of a drug, that frailty is measured at baseline and as an outcome. Preclinical models that replicate the age, frailty, duration of exposure, comorbidities, and co-medications of the proposed patients may improve translation. We highlight the potential application of recent technologies, such as physiologically based pharmacokinetic-pharmacodynamic modeling informed by frailty biology, and Artificial Intelligence, to inform personalized medicine for older patients. Considerations for the rapidly aging populations in low- and middle-income countries related to health-care and clinical trials are outlined. Involving older adults, their caregivers and health-care providers in all phases of research should improve drug development, evaluation, and outcomes for older adults internationally.

Kalium 3.0 is a comprehensive depository of natural, artificial, and labeled polypeptides acting on potassium channels.

Here, we introduce the third release of Kalium database (http://kaliumdb.org/), a manually curated comprehensive depository that accumulates data on polypeptide ligands of potassium channels. The major goal of this amplitudinous update is to summarize findings for natural polypeptide ligands of K+ channels, as well as data for the artificial derivatives of these substances obtained over the decades of exploration. We manually analyzed more than 700 original manuscripts and systematized the information on mutagenesis, production of radio- and fluorescently labeled derivatives, and the molecular pharmacology of K+ channel ligands. In result, data on more than 1200 substances were processed and added enriching the database content fivefold. We also included the electrophysiological data obtained on the understudied and neglected K+ channels including the heteromeric and concatenated channels. We associated target channels in Kalium with corresponding entries in the official database of the International Union of Basic and Clinical Pharmacology (IUPHAR). Kalium was supplemented with an adaptive Statistics page, where users are able to obtain actual data output. Several other improvements were introduced, such as a color code to distinguish the range of ligand activity concentrations and advanced tools for filtration and sorting. Kalium is a fully open-access database, crosslinked to other databases of interest. It can be utilized as a convenient resource containing ample up-to-date information about polypeptide ligands of K+ channels. This article is protected by copyright. All rights reserved.

Development, evaluation and use of COVID-19 vaccines in older adults: Preliminary principles for the pandemic and beyond.

Development, evaluation and use of COVID-19 vaccines in older adults: Preliminary principles for the pandemic and beyond.

Centrosomal Localization of RXRα Promotes PLK1 Activation and Mitotic Progression and Constitutes a Tumor Vulnerability.

Retinoid X receptor alpha (RXRα), a nuclear receptor of transcription factor, controls various physiological and pathological pathways including cellular growth, proliferation, differentiation, and apoptosis. Here, we report that RXRα is phosphorylated at its N-terminal A/B domain by cyclin-dependent kinase 1 (Cdk1) at the onset of mitosis, triggering its translocation to the centrosome, where phosphorylated-RXRα (p-RXRα) interacts with polo-like kinase 1 (PLK1) through its N-terminal A/B domain by a unique mechanism. The interaction promotes PLK1 activation, centrosome maturation, and mitotic progression. Levels of p-RXRα are abnormally elevated in cancer cell lines, during carcinogenesis in animals, and in clinical tumor tissues. An RXRα ligand XS060, which specifically inhibits p-RXRα/PLK1 interaction but not RXRα heterodimerization, promotes mitotic arrest and catastrophe in a tumor-specific manner. These findings unravel a transcription-independent action of RXRα at the centrosome during mitosis and identify p-RXRα as a tumor-specific vulnerability for developing mitotic drugs with improved therapeutic index.

Advances in Neurobiology and Pharmacology of GPR12.

GPR12 is a G protein-coupled orphan receptor genetically related to type 1 and type 2 cannabinoid receptors (CB1 and CB2) which are ancient proteins expressed all over the body. Both cannabinoid receptors, but especially CB1, are involved in neurodevelopment and cognitive processes such as learning, memory, brain reward, coordination, etc. GPR12 shares with CB1 that both are mainly expressed into the brain. Regrettably, very little is known about physiology of GPR12. Concerning its pharmacology, GPR12 seems to be endogenously activated by the lysophospholipids sphingosine-1-phosphate (S1P) and sphingosyl-phosphorylcholine (SPC). Exogenously, GPR12 is a target for the phytocannabinoid cannabidiol (CBD). Functionally, GPR12 seems to be related to neurogenesis and neural inflammation, but its relationship with cognitive functions remains to be characterized. Although GPR12 was initially suggested to be a cannabinoid receptor, it does not meet the five criteria proposed in 2010 by the International Union of Basic and Clinical Pharmacology (IUPHAR). In this review, we analyze all the direct available information in PubMed database about expression, function, and pharmacology of this receptor in central nervous system (CNS) trying to provide a broad overview of its current and prospective neurophysiology. Moreover, in this mini-review we highlight the need to produce more relevant data about the functions of GPR12 in CNS. Hence, this work should motivate further research in this field.

The IUPHAR Guide to Immunopharmacology: connecting immunology and pharmacology.

SummaryGiven the critical role that the immune system plays in a multitude of diseases, having a clear understanding of the pharmacology of the immune system is crucial to new drug discovery and development. Here we describe the International Union of Basic and Clinical Pharmacology (IUPHAR) Guide to Immunopharmacology (GtoImmuPdb), which connects expert‐curated pharmacology with key immunological concepts and aims to put pharmacological data into the hands of immunologists. In the pursuit of new therapeutics, pharmacological databases are a vital resource to researchers through providing accurate information on the fundamental science underlying drug action. This extension to the existing IUPHAR/British Pharmacological Society Guide to Pharmacology supports research into the development of drugs targeted at modulating immune, inflammatory or infectious components of disease. To provide a deeper context for how the resource can support research we show data in GtoImmuPdb relating to a case study on the targeting of vascular inflammation.

Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs

Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs

Nuclear Factor-kappaB Gates Nav1.7 Channels in DRG Neurons via Protein-Protein Interaction.

SummaryIt is well known that nuclear factor-kappaB (NF-κB) regulates neuronal structures and functions by nuclear transcription. Here, we showed that phospho-p65 (p-p65), an active form of NF-κB subunit, reversibly interacted with Nav1.7 channels in the membrane of dorsal root ganglion (DRG) neurons of rats. The interaction increased Nav1.7 currents by slowing inactivation of Nav1.7 channels and facilitating their recovery from inactivation, which may increase the resting state of the channels ready for activation. In cultured DRG neurons TNF-α upregulated the membrane p-p65 and enhanced Nav1.7 currents within 5 min but did not affect nuclear NF-κB within 40 min. This non-transcriptional effect on Nav1.7 may underlie a rapid regulation of the sensibility of the somatosensory system. Both NF-κB and Nav1.7 channels are critically implicated in many physiological functions and diseases. Our finding may shed new light on the investigation into the underlying mechanisms.

The IUPHAR Pharmacology Education Project.

Online learning, an essential component of most traditional contact-based educational programs, must be of high quality to contribute effectively to learning. The availability of first-class web-based materials is particularly valued by both learners and educators in resource-poor nations. In this Practice article, we introduce the International Union of Basic and Clinical Pharmacology (IUPHAR) Pharmacology Education Project (PEP) (https://www.pharmacologyeducation.org/), a freely accessible online learning resource intended to support education and training in pharmacological sciences worldwide.

Evolution of pharmacology education in India: Past and future.

Pharmacology education has passed through various stages in the evolution sequence due to ever-changing type and repository of drugs as well as technological advancements in the educational processes. This article reviews the journey of evolution of pharmacology education. Pharmacology is relevant component of various curricula in medical, dental, and paramedical courses. A huge number of students learn pharmacology as a subject. Important milestones in evolutionary sequence included revisions and updates in learning objectives, teaching-learning material/methods and assessment in undergraduate (UG) and postgraduate (PG) levels. During this period, a number of pharmacology organizations and associations were formed for the progress of the subject. The inception of Indian Pharmacological Society and International Union of Pharmacology is worth mentioning. There are standardization and unification efforts being done in pharmacology education at national and international levels. The era of animal experimentation is struggling to survive in the new era of animations and simulations. There is increasingly more emphasis on the relevant clinical pharmacy and clinical pharmacology components in the education. The past evolutionary sequences provide leads for future evolutions. New courses and innovations are being designed and implemented to make pharmacology education more meaningful and useful to the new technology-savvy students. A number of innovations in the form of case-based learning, objective-structured practical examination, small group learning, interactive, and integrated methods are being implemented. There is a lot of work being done to introduce a competency-based intergraded curriculum in medical UG and PG courses. All these evolutionary sequences require changing and evolving role of teachers as facilitators.

The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY.

The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, www.guidetopharmacology.org) and its precursor IUPHAR-DB, have captured expert-curated interactions between targets and ligands from selected papers in pharmacology and drug discovery since 2003. This resource continues to be developed in conjunction with the International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS). As previously described, our unique model of content selection and quality control is based on 96 target-class subcommittees comprising 512 scientists collaborating with in-house curators. This update describes content expansion, new features and interoperability improvements introduced in the 10 releases since August 2015. Our relationship matrix now describes ∼9000 ligands, ∼15 000 binding constants, ∼6000 papers and ∼1700 human proteins. As an important addition, we also introduce our newly funded project for the Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb, www.guidetoimmunopharmacology.org). This has been ‘forked’ from the well-established GtoPdb data model and expanded into new types of data related to the immune system and inflammatory processes. This includes new ligands, targets, pathways, cell types and diseases for which we are recruiting new IUPHAR expert committees. Designed as an immunopharmacological gateway, it also has an emphasis on potential therapeutic interventions.

VP25 African Countries Are Working Together To Enhance Medicine Use

INTRODUCTION:The socioeconomic burden of diseases is increasing in Africa. For instance in 2011, 70 percent of the world's human immunodeficiency virus (HIV) population resided in sub-Sahara Africa. There are also growing rates of Antimicrobial Resistance (AMR), which necessitates newer more expensive antibiotics adding to costs. There is also a growing burden of non-communicable diseases (NCDs), three out of four patients with hypertension currently live in low and middle income countries (LMICs), with prevalence rates up to 30 to 45 percent among adults in Africa. Alongside this, up to 70 percent of total healthcare expenditure is spent on medicines in LMICs; much of this out-of-pocket. Consequently, there is an urgent need to strengthen collaborative research to improve medicine use.METHODS:Summary of groups working together in Africa including the Medicines Utilisation Research in Africa (MURIA) group.RESULTS:African Strategies for Health identifies and advocates best practices, as well as works with others to develop sustainable solutions. Pharmacology for Africa (PharfA) organises and promotes pharmacology on the African continent, including research in clinical pharmacology, alongside the International Union of Basic and Clinical Pharmacology (IUPHAR) sub-division. International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Africa co-ordinates activities from the different African country chapters. The South African Health Technology Assessment Society (SAHTAS) is a scientific and professional society for all those who produce, use, or encounter Health Technology Assessment (HTA) in Southern Africa, and the World Health Organization (WHO) International and Regional groups are improving antibiotic drug utilization capabilities in Africa. The MURIA group was established in 2015 (1). Ongoing collaborative research includes (i) initiatives to optimize antibiotic use; (ii) methods to enhance adherence to anti-infective prescribing guidance, (iii) approaches to improve adherence to HIV and NCDs; (iv) researching current anti-hypertensive utilization patterns and knowledge; (v) approaches to enhance Drugs and Therapeutic Committees (DTC) activities, and (vi) strengthening medicine utilization capabilities (2,3). These activities have already strengthened research ties across Africa.CONCLUSIONS:A number of groups are already working across Africa to enhance appropriate medicine use, and should continue. Ongoing MURIA activities include antibiotic point-prevalence studies, ongoing research into infectious diseases, NCDs and DTCs including adherence as well as the third workshop and symposium in Namibia in 2017.

Transcriptome Analysis Reveals That G Protein-Coupled Receptors Are Potential Diagnostic Markers or Therapeutic Targets in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is associated with poor overall survival and the development of more effective therapies is urgently needed. G Protein-Coupled Receptors (GPCRs) represent the largest family of membrane receptors, with an estimated 800 members in humans, and are attractive therapeutic targets, accounting for approximately 30% of targets of marketed drugs. These receptors are key transducers that bind a vast diversity of ligands (e.g. glycoproteins, peptides, amino acids, nucleotides, nucleosides, ions) allowing the cells to adapt to their environment by regulating a wide variety of physiological processes including the control of blood pressure, heart rate, digestive processes, hormone secretion, cell growth and migration, as well as vision and olfaction. Binding to their ligands leads to conformational rearrangements promoting the engagement and modulation of many distinct downstream signaling effectors that are both G protein-dependent and independent.Several GPCRs are critical for cell proliferation and survival, and can be aberrantly expressed in cancer cells. For example, the chemokine receptor CXCR4 plays an important role in metastasis and angiogenesis in breast cancer and many other types of tumors. In AML, CXCR4 overexpression has been associated with poor outcome. Moreover, in vivo mouse studies have shown that the use of a small molecule antagonist of CXCR4 increases the mobilization of AML cells into the peripheral blood and improves the apoptotic effects of chemotherapy. This activity has been explored in a phase I/II clinical study showing that the addition of CXCR4 antagonists to chemotherapy in AML might improve the remission rate. The role of GPCRs in mouse leukemogenesis has also been suggested in a transcriptome analysis of two related leukemia clones that differ in their stem cell frequency. In this study, GPCRs were the most differentially expressed class of genes between the two clones.Currently, an extensive assessment of GPCR expression in human AML is lacking. To address this issue, we studied the expression of GPCRs in a large cohort of AML samples, as well as in normal blood cells, bone marrow cell populations, and cord blood-derived CD34+ cells as controls.The 772 GPCRs analyzed in this study consist of all the GPCR members included in the International Union of Basic and Clinical Pharmacology (IUPHAR) database, as well as 370 olfactory, 24 taste and 4 vomeronasal receptors. RNA sequencing data analysis was performed as previously described (Lavallée et al, Blood 2015 Jan 1;125(1):140-3) and revealed that 240 GPCRs are expressed in cells from this AML cohort. Among these receptors, 30 are upregulated and 19 are downregulated in AML samples compared to CD34+ normal cells. Upregulated GPCRs are enriched in chemokine (CCR1, CXCR4, CCR2, CX3CR1, CCR7, and CCRL2), adhesion (CD97, EMR1, EMR2, and GPR114) and purine (including P2RY2 and P2RY13) receptor sub-families. The downregulated members include adhesion GPCRs such as LPHN1, GPR125, GPR56, CELSR3, and GPR126, protease-activated receptors (F2R and F2RL1), and the Frizzled family receptors SMO and FZD6. Interestingly, specific deregulation was observed in genetically distinct subgroups of AML, a subset of GPCRs being differentially expressed in normal karyotype AML with NPM1 or FLT3 -ITD mutations, and in specimens with Core Binding Factor and MLL rearrangements, thereby representing promising therapeutic targets or diagnostic markers.In conclusion, our results demonstrate that several GPCR members are deregulated in AML with a clear enrichment in distinct classes, providing the rationale for functional assays using available agonists or antagonists to leukemia-enriched GPCRs. Since these receptors are the targets of several US Federal and Drug Administration approved drugs, our results pave the way to explore selected GPCRs as novel AML therapeutic targets. DisclosuresBouvier:American Society of Nephrology: Other: speaker; Domain Therapeutics: Other: Company SAB member, Research Funding; Vertex Pharmaceutical: Research Funding; Ontario Genomic Institute: Other: SAB meeting; BMS: Research Funding; DalCor Pharmaceutics: Other: Company SAB member; Pfizer: Other: Speaker, Research Funding; Novo-Nordisc: Research Funding.

The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands.

The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, http://www.guidetopharmacology.org) provides expert-curated molecular interactions between successful and potential drugs and their targets in the human genome. Developed by the International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS), this resource, and its earlier incarnation as IUPHAR-DB, is described in our 2014 publication. This update incorporates changes over the intervening seven database releases. The unique model of content capture is based on established and new target class subcommittees collaborating with in-house curators. Most information comes from journal articles, but we now also index kinase cross-screening panels. Targets are specified by UniProtKB IDs. Small molecules are defined by PubChem Compound Identifiers (CIDs); ligand capture also includes peptides and clinical antibodies. We have extended the capture of ligands and targets linked via published quantitative binding data (e.g. Ki, IC50 or Kd). The resulting pharmacological relationship network now defines a data-supported druggable genome encompassing 7% of human proteins. The database also provides an expanded substrate for the biennially published compendium, the Concise Guide to PHARMACOLOGY. This article covers content increase, entity analysis, revised curation strategies, new website features and expanded download options.

Editorial introductions

Editorial introductions

Allosteric Modulation of M1 Muscarinic Acetylcholine Receptor Internalization and Subcellular Trafficking

Allosteric modulators are an attractive approach to achieve receptor subtype-selective targeting of G protein-coupled receptors. Benzyl quinolone carboxylic acid (BQCA) is an unprecedented example of a highly selective positive allosteric modulator of the M1 muscarinic acetylcholine receptor (mAChR). However, despite favorable pharmacological characteristics of BQCA in vitro and in vivo, there is limited evidence of the impact of allosteric modulation on receptor regulatory mechanisms such as β-arrestin recruitment or receptor internalization and endocytic trafficking. In the present study we investigated the impact of BQCA on M1 mAChR regulation. We show that BQCA potentiates agonist-induced β-arrestin recruitment to M1 mAChRs. Using a bioluminescence resonance energy transfer approach to monitor intracellular trafficking of M1 mAChRs, we show that once internalized, M1 mAChRs traffic to early endosomes, recycling endosomes and late endosomes. We also show that BQCA potentiates agonist-induced subcellular trafficking. M1 mAChR internalization is both β-arrestin and G protein-dependent, with the third intracellular loop playing an important role in the dynamics of β-arrestin recruitment. As the global effect of receptor activation ultimately depends on the levels of receptor expression at the cell surface, these results illustrate the need to extend the characterization of novel allosteric modulators of G protein-coupled receptors to encapsulate the consequences of chronic exposure to this family of ligands.

Correction to “International Union of Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors”

Correction to “International Union of Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors”

Correction to “International Union of Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors”

In the above article [Bachelerie F, Ben-Baruch A, Burkhardt AM, Combadiere C, Farber JM, Graham GJ, Horuk R, Sparre-Ulrich AH, Locati M, Luster AD, Mantovani A, Matsushima K, Murphy PM, Nibbs R, Nomiyama H, Power CA, Proudfoot AEI, Rosenkilde MM, Rot A, Sozzani S, Thelen M, Yoshie O, and Zlotnik A (