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PubMed2004

Orphan nuclear receptors, PXR and LXR: new ligands and therapeutic potential.

Found in almost all animal species, orphan nuclear receptors (NRs) represent a unique and pivotal resource to uncover new regulatory systems that impact on both health and human diseases. Some of the current marketed drugs are known to target orphan NRs. Examples include the anticancer and retinoic X receptor (RXR)-targeting bexarotene (Targretin, Ligand Pharmaceuticals, Inc.) and the antidiabetic and peroxisome proliferator-activated receptor (PPAR)-gamma-targeting thiaozolidinediones. Several studies presented at a recent conference (Orphan and Nuclear Receptors - New Therapeutic Developments) have provided new insights into several orphan NRs, including the pregnane X receptor (PXR), the liver X receptor (LXR), the constitutive androstane receptor (CAR), PPAR and the RXR. This paper will focus on PXR and LXR, whose recent target gene analysis and ligand identification have raised both promises and practical concerns as to whether or not these receptors can be used as therapeutic targets.

Animals↗
PubMed1999

Activation of the mouse oxytocin promoter by the orphan receptor RORalpha.

Although an increasing number of nuclear orphan receptors have recently been identified, the number of known naturally occurring genes that are directly regulated by orphan receptors is still small. We have shown previously that the gene encoding the neuropeptide oxytocin (OT) is negatively regulated by the orphan receptors chicken ovalbumin upstream transcription factor I (COUP-TFI) and II. Here we show that the mouse OT gene promoter is activated by RORalpha, a representative of the ROR/RZR orphan receptor subfamily. Using promoter/chloramphenicol acetyltransferase reporter constructs in heterologous transfection assays, we determined that RORalpha action induces a <6-fold increase in promoter activity. By 5' and 3' deletion analysis, DNase footprint analysis and electrophoretic mobility shift assays, we found that RORalpha action is mediated by two 14 bp regions centered at 160 and 180 nucleotides upstream of the transcriptional initiation site. Both sites contain significant sequence identities with an established ROR recognition sequence. Mutations in either or both of these sites reduce significantly RORalpha-induced activation of the OT promoter. In view of the strong transcriptional activation exerted by RORalpha on the OT gene promoter and the widespread distribution of different members of the ROR/RZR family, interactions between ROR/RZR isoforms and the OT gene may form part of the multifactorial regulatory mechanisms that control OT gene expression in different tissues.

Animals↗
PubMed1985

Orphan drug development in the United States.

Drug research and development in the U.S. tends to focus on drugs to treat common diseases because of the anticipated return on investment. To stimulate pharmaceutical manufacturers to pursue the development of drugs for rare conditions, the Orphan Drug Act was enacted by Congress on January 4, 1983. Under the provisions of this Act, the FDA can make recommendations on the investigations necessary for marketing approval; exclusive marketing privileges can be obtained; tax credits for expenses incurred are allowed; availability of orphan drugs on an investigational basis is encouraged; and the Orphan Product Board is established for the coordination of research efforts and their reimbursement. The effects of this legislation are evident in the continuing increase in orphan drug designations.

Drug Evaluation↗
PubMedDate not supplied

Orphan Drug Act on congressional agenda.

In 1983, Congress passed the Orphan Drug Act to encourage development of pharmaceuticals used in the treatment or diagnosis of diseases that occur so rarely that there is no financial incentive for development of these so-called "orphan drugs." The Act established, among other things, exclusive marketing rights on unpatentable orphan drugs for a period of seven years and a tax credit equal to 50 percent of the cost of conducting human clinical trials. It also authorized the Secretary of Health and Human Services (HHS) to make grants and enter into contracts to reduce the costs of clinical testing in orphan drug development.

Drug Industry↗
PubMed2004

Understanding orphan drug regulations: an EU and U.S. comparative analysis.

Whereas orphan regulations exist in almost all ICH regions, they may correspond to significantly different types of reality in terms of principles and regulatory requirements. The apparent similarity in regulations may lead to misunderstanding and cultural gaps between sponsors and regulatory authorities. Based on the European and the US experience, we decipher the main points stumbling blocks that US sponsor may strike when applying for an orphan designation in the EU. An update of the orphan drugs designations is provided as well as the upcoming challenges that orphan regulations will meet with the development of pharmaco-genomics and personalized medicines.

Drug Industry↗
PubMed1991

[Orphan drugs].

Diseases lacking in satisfactory therapies, named orphans (over 60% of the known), raise the problem of the availability of new drugs to be discovered and evaluated on toxicological and clinical bases. The estimated cost for the full development of a drug makes it not profitable (and therefore orphan drug) in the case of rare diseases and the typical diseases of developing countries. The USA with the Orphan Drug Act have faced the former, whereas WHO with the "Tropical Diseases Research" programme has faced the latter. Uncommon formulations and dosages of known substances and products no longer marketed as non-profitable are considered orphans drugs as well.

Centers for Disease Control and Prevention, U.S.↗
PubMed1995

Functional role and sequence analysis of a lymphocyte orphan opioid receptor.

Pharmacological evidence indicates that lymphocytes express opioid receptors, but this finding has been questioned. By DNA sequencing of reverse transcription-polymerase chain reaction products, we have found that mouse lymphocytes express mRNA encoding an orphan opioid receptor. These mRNA transcripts were detected in the CD4+, CD8+, and CD4- CD8- lymphocyte subpopulations. Northern blot analysis confirmed that splenic lymphocytes express a 1.5-kb orphan opioid receptor mRNA. Fifteen bases encoding Tyr71-Arg75 in the first intracellular loop are alternatively spliced, suggesting that orphan opioid receptor mRNA encodes two receptor subtypes. Treatment of lipopolysaccharide-stimulated lymphocytes with orphan opioid receptor antisense oligonucleotides suppressed polyclonal IgG and IgM production by 50%. Our results provide direct evidence that lymphocytes express an opioid-like receptor gene, and suggest that this receptor plays a functional role in immunocompetence.

Amino Acid Sequence↗
PubMed1995

The nuclear hormone-receptor family in the brain: classics and orphans.

Nuclear hormone receptors comprise a superfamily of over 40 transcription factors. About half of them are classical receptors for lipophilic ligands such as steroids and vitamins. Almost all of these true receptors are present in the brain, where they transduce chemical signals from endocrine organs or signals of nutritional origin into cellular responses. The other members resemble the classical receptors in structure, but have no known ligands, and are hence called 'orphan receptors'. The issue of whether ligands for nuclear orphan receptors exist is controversial. Evidence is emerging that orphan receptors might be activated by signal transduction pathways or might be constitutive enhancers or repressors that interact with the classical receptors. Thus, nuclear orphan receptors are placed in strategic positions in the regulation of gene expression in the nervous system.

Animals↗
PubMed2005

Orphan GPCRs and their ligands.

Due to their diversity, G-protein-coupled receptors (GPCRs) are major regulators of intercellular interactions. They exert their actions by being activated by a vast array of natural ligands, referred to in this article as "transmitters". Yet each GPCR is highly selective in its ligand recognition. Traditionally, the transmitters were found first and served to characterize the receptors pharmacologically. Since the end of the 1980s, however, it is the GPCRs that are first to be found because they are identified molecularly by homology screening approaches. But the GPCRs found this way suffer of one drawback, they lack their natural transmitters, they are "orphan" GPCRs. Searching for transmitters of orphan GPCRs has given birth to the reverse pharmacology approach that uses orphan GPCRs as targets to identify their transmitters. The most salient successes of the reverse pharmacology approach were the discoveries of 9 novel neuropeptide families. These have enriched our understanding of several important behavioral responses. But the application of reverse pharmacology has also led to some surprising results that question some basic pharmacological concepts. This review aims at describing the history of the orphan GPCRs and their impact on our understanding of biology.

Animals↗
PubMed2005

Orphan nuclear receptors adopted by crystallography.

Of the large nuclear hormone receptor superfamily of proteins, orphan nuclear receptors have remained a mystery owing to their lack of identified ligands and their constitutive nature. Now, structures of several ligand-binding domains of orphan receptors have provided some surprising insights that were not anticipated from molecular studies. Therefore, most orphan nuclear receptors have now been 'adopted' and their regulation has been shown to range from true ligand-independence to highly promiscuous ligand-dependence. Former orphan receptors have been found to contain ligand-binding pockets that range in volume from vast (>1600A3) to non-existent and have been shown to generate surface AF2 motifs that range from being multifunctionally active to distinctly inactive. Insights from these new structures illustrate how powerful a structural biology approach can be when integrated with molecular and cellular physiology.

Animals↗
PubMed2006

'Telling the truth is the best thing': teenage orphans' experiences of parental AIDS-related illness and bereavement in Zimbabwe.

Zimbabwe is one of the countries most affected by HIV/AIDS, and as elsewhere in southern Africa, the impact on children and young people living in affected households is significant. Loss is highly complex and dependent on developmental stage, resilience, quality of care, and social support networks, and often includes a progression of experiences from the onset of a parent's or caregiver's illness, through to the aftermath of death. For several reasons, AIDS-related bereavement is likely to be especially complicated and difficult to accommodate. Understandings of bereavement and grief among African children, and adults' responses to orphans' psychological difficulties, remain under-developed. This paper focuses on the narratives of older children in their teens, who have experienced parental AIDS-related illness and death in six sites in Zimbabwe. A key finding is that, while many orphaned teenagers desire direct communication with adults about parental illness and death, adults themselves--whether the sick parent, other relatives in the household or a caregiver following parental loss--are often ill-equipped to identify and manage children's distress positively. While most existing psychosocial interventions focus on bereaved children, this paper suggests that, in order to create an enabling environment for orphans, building the capacity of key adults in orphans' lives, particularly surviving relatives, caregivers, and teachers to address emotional issues relating to parental loss constructively is an essential, but neglected, area of programming.

Adolescent↗
PubMed2004

Digging deep into the pockets of orphan nuclear receptors: insights from structural studies.

Nuclear receptors comprise a large family of proteins that shares a common structure and mechanism of action. Members of this family, first cloned 20 years ago, are regulated by small lipophilic signaling molecules such as steroid hormones, retinoids and thyroid hormone. More recently, the characterization of proteins that resemble nuclear receptors (referred to as orphan receptors) has resulted in the determination of novel signaling pathways. However, many orphan-receptor ligands remain unidentified, and recent structural studies of the binding domains for orphan-receptor ligands suggest that not all of these receptors use ligand binding in a classical way. Notably, it is now evident that some orphan receptors lack the capacity for ligand binding, which suggests that they are regulated by alternative, ligand-independent mechanisms.

Animals↗
PubMed1998

Nuclear orphan receptors COUP-TFII and Ear-2: presence in oxytocin-producing uterine cells and functional interaction with the oxytocin gene promoter.

We have previously demonstrated that the oxytocin (OT) gene is expressed in the rat uterine epithelium and that its expression is upregulated in vivo and in vitro by estrogen. This hormonal regulation is mediated by a hormone response element (HRE) located in the OT gene promoter. Here we show that the same OT-HRE is also capable of interacting with two novel members of the orphan nuclear receptor family, rat COUP-TFII and Ear-2, and that this interaction antagonizes the estrogenic induction of the OT promoter. By Northern blot analysis and immunocytochemistry, using specific cDNA probes and antibodies, respectively, we demonstrate furthermore that both orphan receptors are expressed in uterine epithelial cells. Therefore, the present findings indicate that uterine OT gene expression is under stimulatory as well as inhibitory influences which are both mediated by the same HRE. More detailed analysis of the sequences necessary for estrogen receptor action and for orphan receptor action, using site-directed mutagenesis, revealed that the specific recognition sequences are overlapping but distinct: whereas the (imperfect) palindromic structure of the HRE constitutes the estrogen response element (ERE), orphan receptor action relies on an underlying direct TGACC repeat which forms part of the OT-HRE structure and overlaps with the estrogen response element.

Animals↗
PubMed2002

'Diagnostic orphans' among young adult cannabis users: persons who report dependence symptoms but do not meet diagnostic criteria.

OBJECTIVE: To examine the characteristics of 'diagnostic orphans' among cannabis users-those who report one or two symptoms of DSM-IV dependence but do not meet diagnostic criteria for DSM-IV abuse or dependence. METHOD: Data were collected from a representative population cohort of 1601 young adults aged 20-21 years. Those who reported that they had used cannabis at least weekly at some point within the past year were assessed for symptoms of DSM-IV cannabis abuse and dependence using the Composite International Diagnostic Interview. RESULTS: Approximately 2.8% of the cohort could be classified as diagnostic orphans, with another 3.0 and 7.5% meeting criteria for abuse and dependence, respectively. Diagnostic orphans were: similar to those who met criteria for cannabis abuse or dependence in terms of demographic characteristics; similar to those who met criteria for cannabis abuse in terms of cannabis use patterns; and similar to those who met criteria for abuse and dependence in their rates of heavy alcohol use and DSM-IV alcohol dependence. However, they did not appear to have elevated rates of illicit drug use or mental health problems compared to non users. CONCLUSIONS: Diagnostic orphans reported using cannabis in a manner similar to persons meeting criteria for cannabis abuse, and had similar rates of alcohol dependence and other illicit drug use. Strict adherence to DSM-IV diagnoses of abuse and dependence may overlook a substantial proportion of young persons who experience cannabis-related problems. There is a need to consider (a) subthreshold levels of cannabis-related problems among those seeking treatment for other problems; and (b) interventions for this group to prevent escalation of such problems.

Adult↗
PubMed2001

Orphan G protein-coupled receptors in the CNS.

The majority of genes encoding G protein-coupled receptors were isolated by methods based on sequence similarities found throughout this family. Experimental techniques have exploited these similarities (including low-stringency hybridization, polymerase chain reaction and electronic database searching) to identify genes encoding many pharmacologically recognized receptors and their subtypes. Homology-based searches have revealed receptors for which the endogenous ligands were unknown and these were named orphan receptors. Many orphan receptors are expressed in the brain, suggesting the existence of unidentified neurotransmitters. Methods used to identify ligands for these orphan receptors resulted in the identification of novel ligands and succeeded in pairing previously identified ligands with their receptors. Similar successful strategies are required to characterize the physiological and pathological importance of the remaining orphan receptors to facilitate the discovery of novel drugs for these systems.

Animals↗
PubMed2006

The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization.

One-third of the approximately 400 nonodorant G protein-coupled receptors (GPCRs) are still orphans. Although a considerable number of these receptors are likely to transduce cellular signals in response to ligands that remain to be identified, they may also have ligand-independent functions. Several members of the GPCR family have been shown to modulate the function of other receptors through heterodimerization. We show that GPR50, an orphan GPCR, heterodimerizes constitutively and specifically with MT(1) and MT(2) melatonin receptors, using biochemical and biophysical approaches in intact cells. Whereas the association between GPR50 and MT(2) did not modify MT(2) function, GPR50 abolished high-affinity agonist binding and G protein coupling to the MT(1) protomer engaged in the heterodimer. Deletion of the large C-terminal tail of GPR50 suppressed the inhibitory effect of GPR50 on MT(1) without affecting heterodimerization, indicating that this domain regulates the interaction of regulatory proteins to MT(1). Pairing orphan GPCRs to potential heterodimerization partners might be of clinical importance and may become a general strategy to better understand the function of orphan GPCRs.

Arrestins↗
PubMed2002

Activation of transcription through the ligand-binding pocket of the orphan nuclear receptor ultraspiracle.

The invertebrate nuclear receptor, ultraspiracle (USP), an ortholog of the vertebrate RXR, is typically modelled as an orphan receptor that functions without a ligand-binding activity. The identification of a ligand that can transcriptionally activate USP would provide heuristic leads to the structure of potentially high affinity activating compounds, with which to detect unknown regulatory pathways in which this nuclear receptor participates. We show here that the application of the sesquiterpenoid methyl epoxyfarnesoate (juvenile hormone III) to Sf9 cells induces transcription from a transfected heterologous core promoter, through a 5'-placed DR12 enhancer to which the receptor ultraspiracle (USP) binds. Isolated, recombinant USP from Drosophila melanogaster specifically binds methyl epoxyfarnesoate, whereupon the receptor homodimerizes and changes tertiary conformation, including the movement of the ligand-binding domain alpha-helix 12. Ligand-binding pocket point mutants of USP that do not bind methyl epoxyfarnesoate act as dominant negative suppressors of methyl epoxyfarnesoate-activation of the reporter promoter, and addition of wild-type USP rescues this activation. These data establish a paradigm in which the USP ligand-binding pocket can productively bind ligand with a functional outcome of enhanced promoter activity, the first such demonstration for an invertebrate orphan nuclear receptor. USP thus establishes the precedent that invertebrate orphan receptors are viable targets for development of agonists and antagonists with which to discern and manipulate transcriptional pathways dependent on USP or other orphan receptors. The demonstration here of these functional capacities of USP in a transcriptional activation pathway has significant implications for current paradigms of USP action that do not include for USP a ligand-binding activity.

Amino Acid Motifs↗
PubMed1995

Identification of a new enhancer in the promoter region of human TR3 orphan receptor gene. A member of steroid receptor superfamily.

Human TR3 orphan receptor is a member of the steroid/thyroid hormone receptor superfamily and is the human homologue of the proteins encoded by the rat NGFI-B and mouse nur77 genes. These genes are induced rapidly by androgens/growth factors and may have functions related to cell proliferation, differentiation, and apoptosis. To investigate the TR3 orphan receptor gene transcriptional regulation, a 2.3-kilobase genomic DNA fragment containing the TR3 orphan receptor gene promoter region was isolated, sequenced, and characterized. Sequence homology search within this promoter region revealed some potential cis-acting elements such as cAMP response element, interleukin-6 response element, estrogen response element, and GC box. Deletion analysis and chloramphenicol acetyltransferase assay also showed a novel cis-acting element of TR3 orphan receptor gene (NCAE-TR3), 200-181 base pairs upstream of the transcriptional start site. Gel retardation assay further demonstrated that some nuclear factors can bind to this NCAE-TR3. Together, our data suggest that NCAE-TR3 could be a new enhancer element associated with the transcription of an early response gene for mitogenesis and apoptosis.

Animals↗