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RESEARCH PROGRAM
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Research Units
Similar research programs:
- 1 - SYNTHESIS AND EVALUATION OF NOVEL LIGANDS FOR THE PERIPHERAL BENZODIAZEPINE RECEPTOR USEFUL FOR CLARIFYING ITS PHYSIO-PHARMACOLOGICAL AND DIAGNOSTIC ROLE
- 2 - BEHAVIOURAL, CELLULAR AND MOLECULAR EFFECTS OF ENDOGENOUS ACYLETHANOLAMIDE
- 3 - Design, synthesis and preliminary bio-pharmacological evaluation of ligands useful for the development of drugs for neurodegenerative pathologies in the C.N.S. - A multireceptorial approach.
- 4 - Peripheral benzodiazepine receptor ligands as new apoptosis inducers useful in tumoral therapeutic strategies.
- 5 - Role of endocannabinoids in megakaryocyte differentiation and platelet function
- 6 - The dysregulation of the Hypotalamic-pituitary-gonadal (HPG) axis in the pathogenesis of Alzheimer’s disease: molecular mechanisms and correlation with membrane cholesterol and membrane microdomains organization
- 7 - Design and Synthesis of receptors/enzymes ligands for the development of CNS drugs with antiischaemic/neurprotective and modulatory action.
- 8 - CELL CYCLE CONTROL BY LIGANDS OF NUCLEAR RECEPTORS
- 9 - Somatostatin and related peptides: distribution, biological effects, and characterization of transgenic models
- 10 - Novel CNS Acting Agents: Advanced Medicinal Chemistry Approaches Directed to the Modulation and Characterization of CNS Receptor Pathways
Scientific and education field classification
- Field: Scienze chimiche
- Field: Scienze biologiche
International Patent Classification
Geographical classification
- Region: Sardegna
Bibliografia
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Keywords
PERIPHERAL BENZODIAZEPINE RECEPTOR (PBR), HYDROPHILIC PBR LIGANDS, NEUROSTEROIDOGENESIS, IMIDAZOPYRIDINES, ANTITUMOR DRUG-PBR LIGAND CONJUGATES, DRUG TARGETING AND DELIVERY, RECEPTOR VISUALIZATION; PET, GABA-A RECEPTORS, MITOCHONDRIASYNTHESIS AND PHARMACOLOGICAL CHARACTERIZATION OF NOVEL COMPOUNDS WITH SELECTIVITY FOR THE PERIPHERAL BENZODIAZEPINE RECEPTOR USEFUL FOR THE MODULATION OF NEUROSTEROIDOGENESIS, DIAGNOSIS OF NEURODEGENERATIVE DISORDERS, AND ANTITUMOR DRUG DELIVERY
Università degli Studi di CagliariAbstract
Recent studies have demonstrated that the peripheral benzodiazepine receptor (PBR) plays a number of fundamental roles a cellular level, and among other, in the regulation of the synthesis of steroids. Distinct from the “central” benzodiazepine receptor (CBR), PBR is expressed on the mitochondrial membrane, where it controls cholesterol translocation inside the mitochondrion, both in brain (glial and neuronal cells) and peripheral endocrine organs. Steroids, derived from the metabolism of progesterone which are defined “neurosteroids”, such as allopregnanolone and THDOC, are known to induce marked antistress and anxiolytic effects, which are due to their membrane action through the facilitation of the fast inhibitory neurotransmission mediated by gamma-aminobutyric acid type A (GABA-A) receptors in the Central Nervous System. Physiological and pathological fluctuations in neurosteroid concentrations are thought to have important consequence in influencing and modulating emotional states as well as can play a role in the homeostatic processes and neuronal plasticity which are activated in order to counteract and regulate an excessive level of neuronal excitability triggered by various stimuli such as acute stress.Other studies have demonstrated that PBR expression can be greatly enhanced in different physiological and pathological conditions, such as in several neurodegenerative disorders like Alzheimer’s and Huntington’s diseases. Furthermore, high level of PBR >>>
Principal Investigator
Enrico Sanna Università degli Studi di CAGLIARIResearch Objectives
The peripheral type of benzodiazepine receptors (PBRs) are receptors distinct from the central type of benzodiazepine receptors (CBR) which are associated to GABA-A receptors, and are expressed on the mitochondrial membrane of glial and neuronal cells as well as in cells of peripheral organs such as adrenals, testis, ovary, lungs, liver, heart, and other circulating cells such as platelets, lymphocytes and erythrocytes. PBRs are involved in a number of cellular functions such as regulation of cell proliferation, immune response, cholesterol transport, porphyrin transport and biosynthesis of heme, oxidative processes, and programmed cell death. In addition, another important physiological role played by PBRs is to promote steroidogenesis. In fact, these receptors facilitate the translocation of cholesterol from intracellular sites to the inner mitochondrial membrane, where this precursor is oxidized to pregnenolone. Thus, this process is the rate-limiting step in the synthesis of steroids. Two reduced metabolites of progesterone, allopregnanolone and THDOC, are known to produce, through a positive modulatory action at the GABA-A receptor, pharmacological effects similar to those of benzodiazepines and barbiturates, suggesting that these hormones are among the most important endogenous regulators of emotional states. Furthermore, it is thought that physiological fluctuations of plasma and brain levels of these hormones might determine, through their influence on GABA-A >>>Timescale
24 monthsNational and international background
The peripheral benzodiazepine receptor (PBR), discovered originally because it binds the benzodiazepine diazepam with relatively high affinity (1), is structurally and functionally distinct form the central type of benzodiazepine receptor (CBR), which is a site associated to GABAA receptor complex localized mainly in the central nervous system (CNS). Structurally, PBR is a multimeric complex composed by 3 different subunits. A 18-kDa receptor protein, whose aminoacid sequence (169 AA) presents a 80% homology among different species (human, bovine, murine); hydropathic analysis of primary aminoacid sequence reveals the presence of 5 transmembrane domains, an amino-terminal oriented towards the mitochondrial intermembrane cleft, and a carboxy-terminal oriented towards the cell cytoplasm. This subunit (18-kDa) is associated with 2 other proteins, one of which is a 32-kDa protein that forms a voltage-dependent anion channel required for benzodiazepine binding, and the second is a 30-kDa protein transporter of adenine nucleotides with unknown function (2,3). VDAC is an ion channel of high conductance and limited ion selectivity, localized in the external mitochondrial membrane, in particular on the sites of contact between the external and internal membrane. The adenine nucleotide transporter is localized in the internal mitochondrial membrane.Although PBR is present in most tissues examined (for example, lungs, heart, skeletal muscles, platelets, lymphocytes, red blood >>>
