Pharmaceutica acta Helvetiae最新文献

{"title":"The ciliary neurotrophic factor and its receptor, CNTFRα","authors":"Mark W Sleeman, Keith D Anderson, Philip D Lambert, George D Yancopoulos, Stanley J Wiegand","doi":"10.1016/S0031-6865(99)00050-3","DOIUrl":"10.1016/S0031-6865(99)00050-3","url":null,"abstract":"<div><p><span>Ciliary neurotrophic factor<span> (CNTF) is expressed in glial cells within the central and peripheral nervous systems. CNTF stimulates gene expression, cell survival or differentiation in a variety of neuronal cell types such as sensory, sympathetic, ciliary and motor neurons. In addition, effects of CNTF on oligodendrocytes as well as denervated and intact skeletal muscle have been documented. CNTF itself lacks a classical signal peptide<span> sequence of a secreted protein, but is thought to convey its cytoprotective effects after release from adult glial cells by some mechanism induced by injury. Interestingly, mice that are homozygous for an inactivated CNTF gene develop normally and initially thrive. Only later in adulthood do they exhibit a mild loss of motor neurons with resulting muscle weakness, leading to the suggestion that CNTF is not essential for neural development, but instead acts in response to injury or other stresses. The CNTF receptor complex is most closely related to, and shares subunits with the receptor complexes for interleukin-6 and </span></span></span>leukemia inhibitory factor<span><span><span>. The specificity conferring α subunit of the CNTF complex (CNTFRα), is extremely well conserved across species, and has a distribution localized predominantly to the nervous system and skeletal muscle. CNTFRα lacks a conventional transmembrane domain and is thought to be anchored to the cell membrane by a glycosyl-phosphatidylinositol linkage. Mice lacking CNTFRα die perinatally, perhaps indicating the existence of a second developmentally important CNTF-like ligand. Signal transduction by CNTF requires that it bind first to CNTFRα, permitting the recruitment of gp130 and LIFRβ, forming a tripartite receptor complex. CNTF-induced heterodimerization of the β </span>receptor subunits<span><span> leads to tyrosine phosphorylation (through constitutively associated JAKs), and the activated receptor provides docking sites for SH2-containing signaling molecules, such as </span>STAT proteins. Activated STATs dimerize and translocate to the nucleus to bind specific DNA sequences, resulting in enhanced transcription of responsive genes. The </span></span>neuroprotective<span><span> effects of CNTF have been demonstrated in a number of in vitro cell models as well as in vivo in mutant mouse strains which exhibit motor </span>neuron degeneration<span>. Intracerebral administration of CNTF and CNTF analogs has also been shown to protect striatal output neurons in rodent and primate models of Huntington's disease. Treatment of humans and animals with CNTF is also known to induce weight loss characterized by a preferential loss of body fat. When administered systemically, CNTF activates downstream signaling molecules such as STAT-3 in areas of the hypothalamus which regulate food intake. In addition to its neuronal actions, CNTF and analogs have been shown to act on non-neuronal cells such as glia, hepatocytes, skeletal muscle","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 265-272"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00050-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The RET receptor tyrosine kinase: activation, signalling and significance in neural development and disease","authors":"Ivor Mason","doi":"10.1016/S0031-6865(99)00048-5","DOIUrl":"10.1016/S0031-6865(99)00048-5","url":null,"abstract":"<div><p><span>The RET receptor tyrosine kinase<span><span> was first identified in a screen for human oncogenes and has subsequently been linked to several human syndromes: Hirschprung's disease, multiple endocrine neoplasia types 2A and 2B and familial </span>thyroid carcinoma. Interestingly, all of the tissues affected by mutations in </span></span><em>RET</em><span><span><span><span><span><span> are derived from the neural crest during development. RET transduces a signal following activation by ligands of the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophins which currently comprises GDNF, neuturin (NTN), </span>artemin (ART) and </span>persephin (PSP). To activate RET they form a tripartite complex with RET and a member of a family of four extracellular, GPI-linked </span>alpha receptors (GFRα1–4). Specificity is achieved by each GFRα binding only one member of the GDNF family with high affinity. Current evidence indicates that signal transduction by RET activates several second messenger systems including the PLCγ, Ras, JNK and </span>inositol phosphate<span> pathways. Targeted mutagenesis in </span></span>transgenic mice<span> has shown that Ret, GFRα1 and GDNF are required for multiple developmental events including development of the enteric nervous system (ENS) affected in Hirschsprung's disease. We describe experiments in chick neural crest cells which provide evidence for the normal function of RET and the basis of the defect in Hirschsprung's disease.</span></span></p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 261-264"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00048-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imidazoline receptors: a challenge","authors":"Pascal Bousquet,&nbsp;Véronique Bruban,&nbsp;Stephan Schann,&nbsp;Josiane Feldman","doi":"10.1016/S0031-6865(99)00051-5","DOIUrl":"10.1016/S0031-6865(99)00051-5","url":null,"abstract":"<div><p>The hypotensive effect of imidazoline-like drugs (IMs) directly injected into the rostroventrolateral part of the brainstem (NRL/RVLM) was shown to involve non-adrenergic imidazoline specific receptors (IRs). Some IMs caused hypotension when injected there, irrespective of their affinity and selectivity for any α-adrenoceptor subtype. Compounds, such as LNP 509, S 23515, S 23757 or benazoline with very high selectivities for IRs over α₂-adrenoceptors (A₂Rs), became available recently. Some of these compounds (LNP 509, S 23515) caused hypotension when injected alone into the NRL/RVLM region. Nevertheless, high selectivity for IRs will not predict by its own the capability of IMs to elicit hypotension as some of these substances behaved as antagonists towards the hypotensive effects of the latter. As far as hybrid drugs, i.e., with mixed binding profiles (I₁/α₂), were concerned, a significant correlation has been reported between their central hypotensive effect and their affinity for IRs. Imidazoline antagonists, such as idazoxan, were repeatedly shown to competitively prevent and reverse the centrally induced hypotensive effect of IMs. The sole stimulation of A₂Rs within the NRL/RVLM region was not sufficient to decrease blood pressure as much as IMs did, as shown by the lack of significant blood pressure lowering effect of α-methylnoradrenaline (α-MNA). No correlation was observed between affinity of IMs for A₂Rs and their central hypotensive effects. It is also noticeable that yohimbine, an A₂Rs antagonist, was repeatedly shown to abolish the hypotensive effect of hybrids but usually in a non-competitive manner. Mutation of A₂Rs was shown to prevent the hypotensive effects of centrally acting drugs. It is concluded that (i) drugs highly selective for I₁Rs over A₂Rs can reduce blood pressure by their own; (ii) the central hypotensive effect of IMs needs implication of IRs and appears to be facilitated by additional activation of A₂Rs; and (iii) this effect requires intact A₂Rs along the sympathetic pathways.</p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 205-209"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00051-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Receptors in cardiovascular disease: review and introduction","authors":"Amedeo Leonardi,&nbsp;Giorgio Sironi,&nbsp;Gianni Motta","doi":"10.1016/S0031-6865(99)00029-1","DOIUrl":"10.1016/S0031-6865(99)00029-1","url":null,"abstract":"<div><p><span>Despite recent encouraging declines, cardiovascular disease (CVD) is still responsible for about 50% of premature death in the Western industrialized countries, greater than cancer, AIDS and accidents, combined. Different aspects of the disease have been considered and the main currently available and possible future drugs whose effect is based on interaction with a receptor have been reviewed. Catecholamines receptors<span> ligands, mainly β-blockers, and the new angiotensin II antagonists represent the most important classes among the established therapies. Investigational approaches such as the oral </span></span>glycoprotein<span> GPIIb/IIIa antagonists and endothelin<span>, adenosine and neuropeptide Y receptors ligands are discussed. Receptorology represents just a part of the therapeutical approach to CVD, where other classes of drugs with enzyme or ionic channel based mechanisms are largely used and innovative therapies based on the most advanced research techniques could early become reality.</span></span></p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 157-161"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00029-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural aspects of high affinity ligands for the α4β2 neuronal nicotinic receptor","authors":"Michael J. Dart,&nbsp;James T. Wasicak,&nbsp;Keith B. Ryther,&nbsp;Michael R. Schrimpf,&nbsp;Ki H. Kim,&nbsp;David J. Anderson,&nbsp;James P. Sullivan,&nbsp;Michael D. Meyer","doi":"10.1016/S0031-6865(99)00023-0","DOIUrl":"10.1016/S0031-6865(99)00023-0","url":null,"abstract":"<div><p><span>Neuronal nicotinic acetylcholine receptors (nAChRs) are a heterogeneous family of related ion channels that are widely distributed throughout the central and peripheral nervous systems. They all share a common architecture of five subunit proteins that combine at the cell surface to create a ligand-gated cation permeable pore. Significant effort is currently being expended by medicinal chemistry teams to synthesize ligands that exhibit selectivity for central over peripheral nAChR subtypes. Within the CNS, multiple nAChR subtypes are recognized, and the discovery of ligands exhibiting selectivity among these subtypes offers an opportunity for the development of novel therapeutic agents. The α4β2 subtype is one of the most abundant nAChR subtypes within the CNS, and has been the primary focus of high affinity ligand design. Nicotine (</span><strong>1</strong><span>), and more recently, epibatidine (</span><strong>2</strong><span>) have served as structural templates for the design of the majority of active compounds. Although the diversity of nAChR ligands is growing, the structural requirements necessary for high affinity binding with the α4β2 receptor remain poorly understood. The putative pharmacophoric elements common to all potent α4β2 ligands include (1) a basic or quaternized nitrogen atom, and (2) a less basic nitrogen or a carbonyl oxygen that presumably interact with electron rich and electron deficient sites on the receptor, respectively. The family of currently known high affinity analogs consists of a diverse array of azacycles containing a basic amine. Several additional basic amine fragments have been identified, including the pyrrolizidine nucleus (exemplified by </span><strong>8</strong>) and the 2-azabicyclo[2.2.1]heptane skeleton (exemplified by <strong>9</strong>). In addition, we have found that the furo[2,3-<em>b</em>]pyridine heterocycle (compound <strong>10</strong>) serves as useful bioisosteric replacement for the pyridyl substituent of nicotine. A preliminary pharmacophore model is proposed in which a reasonable superposition of the putative pharmacophoric elements of the diverse array of high affinity ligands for the α4β2 nAChR reported herein may be accommodated.</p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 115-123"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00023-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enigmatic receptors","authors":"Livio Brasili","doi":"10.1016/S0031-6865(99)00033-3","DOIUrl":"10.1016/S0031-6865(99)00033-3","url":null,"abstract":"<div><p>The identification of new binding sites raises the problem of defining their role, if any. At times they are shown to be pharmacological receptors, in a strict sense, as they fulfill certain requirements, and a precise physiological role and function, and an endogenous ligand (neurotransmitter) are discovered. At other times, however, neither a clear physiological role nor an endogenous ligand are found, but the term “receptor” is still used, although it may not be a proper one in the conventional pharmacological sense. Furthermore, no clear intracellular signalling transduction pathway is defined and, as a consequence, it is not possible to determine whether drugs binding to these receptors act as agonists or antagonists. What their structure and biological function are and how they mediate the pharmacological effects of ligands may remain for a long time an enigma. The matter, in any case, is of great interest to researchers of different areas, especially to medicinal chemists who foresee novel potential targets for therapeutic interventions. In this meeting one section is dedicated to two examples of this kind of receptors: imidazoline (I) and sigma (σ) receptors.</p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 201-203"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00033-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Index","authors":"","doi":"10.1016/S0031-6865(00)00028-5","DOIUrl":"https://doi.org/10.1016/S0031-6865(00)00028-5","url":null,"abstract":"","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 345-346"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(00)00028-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137323895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological receptors: a century of discovery — and more","authors":"David J Triggle","doi":"10.1016/S0031-6865(99)00046-1","DOIUrl":"10.1016/S0031-6865(99)00046-1","url":null,"abstract":"<div><p>A brief survey of the history of the development of the concept of the pharmacological receptor is presented. From the pioneering concepts of Paul Ehrlich, John Langley and others, receptors are described in terms of their recognition properties, their structures, transducing abilities and the impact of genomics and their role in contributing to genetic diseases. The receptor concept has firmly underpinned our advances in drug development and molecular medicine of the latter half of this century and it is clear that it will continue to drive pharmaceutical developments in the 21st century.</p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 79-84"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00046-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21660173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The α1a and α1b-adrenergic receptor subtypes: molecular mechanisms of receptor activation and of drug action","authors":"Susanna Cotecchia ,&nbsp;Olivier Rossier ,&nbsp;Francesca Fanelli ,&nbsp;Amedeo Leonardi ,&nbsp;Pier G De Benedetti","doi":"10.1016/S0031-6865(99)00031-X","DOIUrl":"10.1016/S0031-6865(99)00031-X","url":null,"abstract":"<div><p>In this chapter we summarize some aspects of the structure-functional relationship of the α1a and α1b-adrenergic receptor subtypes related to the receptor activation process as well as the effect of different alpha-blockers on the constitutive activity of the receptor. Molecular modeling of the α1a and α1b-adrenergic receptor subtypes and computational simulation of receptor dynamics were useful to interpret the experimental findings derived from site directed mutagenesis studies.</p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 173-179"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00031-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Receptors in neurodegenerative diseases, muscarinic cholinergic receptors","authors":"Piero Angeli","doi":"10.1016/S0031-6865(99)00025-4","DOIUrl":"10.1016/S0031-6865(99)00025-4","url":null,"abstract":"","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 131-134"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00025-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}