核受体及其配体的研究进展

核受体（nudear receptors，NRs）是位于细胞核内或与相应配体结合后由胞浆转到细胞核内的一大类受体，属于配体活化的转录因子。对其特异正性或负性的调控是预防和治疗许多疾病的重要手段。该文对几种重要的核受体配体的功能及其构效关系研究进行综述。     

Synthetic retinoids as potential antitumour agents

The retinoids, natural or synthetic derivatives of vitamin A, exhibit a variety of biological effects that may have implications in cancer chemoprevention and therapy. The chemopreventative action of classical retinoids has been ascribed to receptor-mediated modulation of a range of biological processes, including cell differentiation and proliferation. The therapeutic interest of several synthetic retinoids (also known as retinoid-related molecules) is related to their proapoptotic activity, which appears to be independent of the receptor-transactivating activity. This review focuses on the relevant features of recently reported synthetic retinoids, with particular reference to their therapeutic potential and current understanding of the mechanism of action. These agents are structurally heterogeneous compounds, including molecules closely related to natural retinoids and molecules with a retinoid-like structure (e.g., atypical retinoids) that include retinoic acid receptor (RAR) selective compounds or RAR antagonists. Promising agents of this class are adamantyl retinoids because of their apoptotic potency, in vivo antitumour activity and low toxicity. Activity of selected adamantyl retinoids (e.g., CD437, MX3350-1, ST1926) has been reported in models of various tumour types, including ovarian, breast, lung, head/neck squamous carcinoma and melanoma. The best in vivo antitumour efficacy was achieved by a protracted treatment. Orally available molecules (e.g., ST-1926) are the most suitable for this treatment schedule. Synthetic retinoids have shown synergistic interaction in combination with a variety of antitumour agents used in clinical therapy. This evidence is expected to expand the therapeutic options for clinical use of retinoids.     

Synthesis and preliminary evaluation of affinity to retinoic acid receptors for new organosilicon-based retinoids

Facile synthetic routes to new silicon-containing ligands (1–4) for retinoic acid receptors (RARs) are reported. The design of these RAR ligands is based on a pharmacophoric model that divides the molecules into three regions (A, B, and C). The series of ligands is unique in region A due to their acyclic nature and the presence of alkyl-substituted silicon at the core. Substituted silyl groups that are generally viewed as protecting groups are used to fulfill pharmacophore requirements. Various alkyl substituents available on the silicon starting materials afford an opportunity to explore steric effects on binding. In region B of ligands 1–4, a cinnamate moiety maintains some degree of conjugation and planarity in the molecules. A biaryl group used in region B of another series of compounds is reported to lead to RARb selectivity. Finally, region C of the ligands contains a carboxylate group, a well know pharmacophore requirement for RAR ligands. The compounds prepared in this work were found to have micromolar to nanomolar affinity for these medically relevant target receptors. The proposed silane-containing ligands ‘represent a new series of siloacetylenic aryl acids that are worth of further investigation. They may serve as leads for the development of higher-affinity, more receptor-selective agents.     

The retinoids. A review of their clinical pharmacology and therapeutic use

With the introduction of the synthetic retinoids, oral therapy with an acceptable risk/benefit ratio became possible for a variety of skin diseases including severe acne, psoriasis and numerous genodermatoses. This article reviews the clinical pharmacology, mechanisms of action and therapeutic use of the retinoids, particularly isotretinoin (13-cis-retinoic acid) and etretinate. The free aromatic acid of etretinate, etretin, and the new polyaromatic retinoid compounds (arotinoids) are also discussed. Isotretinoin is used clinically for oral therapy of severe acne, but is also recommended for severe Gram-negative folliculitis and rosacea not responding to traditional therapy. The results of several studies have established that acne therapy should be started with 1.0 mg/kg/day for 2 to 3 months after which the daily dosage should be lowered to 0.2 to 0.5 mg/kg/day for another 2 to 3 months. This therapeutic regimen of isotretinoin has proven to be the most successful in preventing relapses. Etretinate is particularly useful for oral therapy of widespread plaque-like, pustular and erythrodermic psoriasis, and of generalised lichen planus, Darier's disease and severe congenital ichthyoses. Whereas pustular forms of psoriasis require a high daily dosage of 1.0 mg/kg/day, erythrodermic psoriasis should be treated with a lower dosage of 0.25 to 0.35 mg/kg/day. In chronic plaque-like psoriasis, a mean daily dosage of 0.5 mg/kg/day over several weeks to months, usually combined with photo(chemo)therapy, tar or dithranol, is recommended. Other indications for oral etretinate therapy are adequately treated with a moderate dosage of 0.4 to 0.75 mg/kg/day. Etretin differs from etretinate in having a much shorter elimination half-life of 2 to 3 days, in contrast to 80 to 100 days after long term administration of etretinate. Moreover, it has not been shown to increase serum cholesterol levels. However, its clinical efficacy is not yet clearly established. Among the arotinoids, arotinoid ethylester (Ro 13-6298) has revealed the best anti-psoriatic and anti-inflammatory effects at extremely low dose levels. Furthermore, no significant elevations of serum lipids have been observed. Taking its prolonged elimination half-life and its efficacy/side effect ratio into account, the drug is comparable to etretinate. The free arotinoid carboxylic acid (Ro 13-7410) is currently undergoing clinical investigation. Another arotinoid, the parent compound Ro 15-0778, has not demonstrated any convincing clinical efficacy in acne or psoriasis, but topical anti-inflammatory effects were evident in some models.(ABSTRACT TRUNCATED AT 400 WORDS)     

Bile acids and derivatives, their nuclear receptors FXR, PXR and ligands: role in health and disease and their therapeutic potential

Bile acids, their physiology and metabolism, their role in carcinogenesis and other major human diseases are recently undergoing significant progress. Starting in 1999 when the orphan nuclear receptor FXR was shown to be specifically activated by bile acids, these compounds became part of the arsenal of ligands of the steroid hormone superfamily of nuclear receptors, including receptors of Vitamin D3, retinoids (RAR, RXR), and thyroid hormone. Another decisive discovery pointed later that the pregnane X-receptor (PXR) is activated by the endogenous toxic lithocholic acid, as well as several xenobiotics and drugs. Bile acids have recently emerged as key regulators of their own metabolism, and of lipid and carbohydrate metabolism. They have important role as promoters of esophageal and colon cancers, cholangiocarcinoma, as well as new implications in breast cancer development and metastasis. This Review will emphasize novel aspects of bile acids, FXR and PXR as regulators of interfaces at cell proliferation and differentiation, cell death, survival, invasion, and metastasis during normal development and cancer progression. Signaling pathways controlled by bile acids will be presented and discussed in relation to their impact on gene expression. The biological and pharmacological significance of bile acids and their recently developed synthetic derivatives and conjugates, as well as new development in the design of FXR agonists and antagonists for clinical applications in cancer prevention and therapy, will be evaluated. This part includes advances in the utilization of bile acid transporters in drug resistance, therapeutic targeting and delivery of anticancer drugs, as well as therapeutic combinations using new bile acid derivatives, sequestrating agents and reabsorption inhibitors, and their limitations.     

Synthetic oligonucleotide combinatorial libraries and their applications

The application of synthetic oligonucleotide combinatorial libraries is described in the studies of triplex DNA. A new method of selection of dispersed (beaded) oligonucleotide combinatorial libraries based on the use of streptavidin magnetic beads is presented. A combinatorial chemistry approach is also proposed for studies of polyaminooligonucleotides.     

Adenosine receptors and their ligands

The regulatory actions of adenosine are mediated via four subtypes of G protein-coupled receptors distinguished as A1, A2A, A2B and A3 receptors. Their presence on basically every cell makes them an interesting target for the pharmacological intervention in many pathophysiological situations. A large number of ligands have been synthesized over the last two decades and provide agonists and antagonists that are more or less selective for the known receptor subtypes. In addition, many radioligands are available in tritiated or radioiodinated form. The comparative pharmacological characterization of all four human adenosine receptor subtypes revealed that some of the compounds thought to be selective from data in other species have unexpected potencies at human receptors. As a result, compounds that exhibit high affinity to only one subtype are an exception. Although the selection of ligands is immense, it is less than satisfying for most subtypes of adenosine receptors.     

Bioactive lipids and their receptors

Recent studies show that several, if not all, degradative products of glycerol- and sphingosine-based lipids are active molecules that play important roles in different signal transduction pathways. The functions and actions of lysophosphatidic acid and sphingosine 1-phosphate, the degradation products of phospholipids and sphingolipids, respectively, have received a great deal of attention during the past few years. These lipid mediators are active through several abundant G protein-coupled receptors that were recently identified and characterized. This review will discuss recent achievements in the area of bioactive lipids.     

Endogenous opioids and their receptors

Since the endogenous opioid peptides bind to more than one of the types of binding sites, it is important to have synthetic compounds that bind almost exclusively at one site. There are now such agonists available but antagonists are still required that interact exclusively with one opioid site. The results obtained with opioid peptides or non-peptides having such qualities will be the physiological basis for a correlation of the binding at mu-, delta- and kappa-receptors with their pharmacological effects. It is important to realize that almost all endogenous opioid ligands are degraded by peptidases and that it is necessary to have synthetic non-toxic inhibitors of those peptidases that play a role in opioid transmission. Related to this problem is the need to develop methods for the study of the release of various endogenous opioid peptides under physiological conditions.     

Adenosine receptors and their modulators

The identification and characterization of adenosine receptors and the development of potent, receptor subtype-selective agonist and antagonists has been an active area of research for the past 20 years.Major recent advances in the field have been the cloning of several adenosine receptor subtypes of different species, including the discovery of a new subtype, designated A3, the discovery and development of new agonists and antagonists particularly those with selectivity for the A2a adenosine receptor, the characterization of signal transduction pathways, and the development of agents which act indirectly on the adenosine receptor system.The present article focusses on aspects of pharmaceutical/medicinal chemistry related to adenosine receptors.     

Opioid receptors and their ligands

This review gives a historical perspective, summarizing approximately 25 years of research on opioids. The "typical" opioid peptides produced in the brain, "atypical" opioids encrypted in milk protein or hemoglobin sequences, and extremely potent and selective opioids of amphibian origin are described. The main focus is on the structure-activity relationship studies of peptide ligands for three main opioid receptor types (micro, delta, kappa), their selectivities and pharmacological activities in vitro. Chemical modifications that led to obtaining potent and selective agonists and antagonists for these receptors are discussed.