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Laboratorio di ricerca

Lab. nameLiBraMedChem 
Principal Investigator Livio Brasili 
ComponentsLivio Brasili  (Principal Investigator )
Silvia Franchini  (Ricercatore )
Claudia Sorbi  (Ricercatore )
Annalisa Tait  (Collaboratore )
Description(1) Synthesis, purification and structural characterization of new ligands for alpha-1 adrenergic (A), 5-HT1A serotoninergic (B), NOP (C), Sigma (D), TAAR receptors (E). Structure-Activity Relationship studies are performed on the basis of biological results obtained by testing the molecules previously designed for each project (A, B, C, D, E) and then produced in our lab. (2) Synthesis, purification and structural characterization of new 1,3-oxathiolane/dioxolane and 1,3-dioxane based nucleoside analogues as potential antiviral/anticancer agents. RATIONALE (1A, 1B): initially introduced for hypertension management, alpha-1 antagonists have become increasingly common for symptomatic treatment of benign prostatic hyperplasia (BPH). The 5-HT1A receptor subtype is involved in a wide range of physiopathological processes. The main limitation of many 5-HT1A receptor ligands is their undesired high affinity for other receptor subtypes such as alpha-1- adrenoceptors (high degree of homology). Recently, our research group has demonstrated that a properly substituted 1,3-dioxolane moiety is a suitable scaffold for developing selective ligands targeting alpha-1 adrenoceptors or 5-HT1A receptors. (1C): the N/OFQ-NOP receptor system is distinct from classical opioid receptors. NOP agonists are being investigated as potential therapeutics for anxiety, cough, and drug abuse. NOP antagonists have been studied for their utility in treating Parkinson's, depression, obesity and learning deficits. Among the neuroleptics tested, spiroxatrine (an alpha-2 adrenergic and 5-HT1A antagonist) was selected as lead compound and we reported on the results of a large SAR study aimed at identifying a new series of triazaspirodecanones as NOP receptor ligands. (1D): sigma receptors are a distinct class from that of opioid too. They are divided into sigma1 and sigma2 subclasses. Several functions for sigma1 receptors have been discovered: modulatory roles on K+ and Ca2+ channels and on dopaminergic, NMDA, serotoninergic, muscarinic neurotransmission, while sigma2 receptors are involved in the regulation of cell proliferation and viability. Despite several selective, high affinity sigma1 ligands are available, sigma2 ligands are not characterized to the same extent. Our aim is to find more potent sigma1 ligands and new, selective sigma2 ligands. (1E): it is expected, for example, that targeting human TAAR1 (trace amine-associated receptor 1) could provide a novel pharmacological approach for several human disorders, such as schizophrenia, depression, attention deficit, hyperactivity disorder, Parkinson's and metabolic diseases. With the aim to identify new molecular entities able to act as ligands for this target, we recently started a research project in this field. RATIONALE (2): together with protease inhibitors (PI), drugs inhibiting the RNA- and DNA-dependent DNA polymerase activity of RT (Reverse Transcriptase) are the major components of highly active antiretroviral therapy (HAART). RT inhibitors belong to two main classes: nucleoside RT inhibitors (NRTIs) and non nucleoside RT inhibitors (NNRTls). The advent of RT inhibitors with higher genetic barriers to the development of resistance and/or novel mechanisms of action promise to further reduce the risk of resistance development. BCH-1230, which has the same sugar configuration of the natural nucleotides, showed two fold greater activity than ddl. We evaluated first the effect on the RT inhibitory activity of a methyl group introduction at position 5 of the 1,3-oxathiolane ring of BCH-1230. Our research in this field (NRTIs synthesis) is still in progress and has produced also 1,3-dioxane and 1,3-dioxolane based derivatives. Furthermore 1,3-dioxolane-based nucleosides are reported to inhibit the growth of hepatocellular and prostate tumours, making them attractive candidates for more detailed medicinal chemistry studies. 
Addressvia Giuseppe Campi, 287 - 41125 Modena 
KeywordsMedicinal/Organic Synthesis, NMR and LC-MS/MS Studies, Receptors, CNS, Nucleosides 
ERC Sectors LS7_3 Pharmacology, pharmacogenomics, drug discovery and design, drug therapy LS7_3 Pharmacology, pharmacogenomics, drug discovery and design, drug therapy LS7_3 Pharmacology, pharmacogenomics, drug discovery and design, drug therapy  
Instrumentationn.1 Microwave, CEM; n. 1 HPLC SP1, Biotage 
Research Lines Drug discovery, analysis, delivery and molecular engineering platforms

Methodologies Various synthetic approaches in the medicinal chemistry field, Different chromatographic purification systems, NMR structural characterization of the synthesized molecules, LC-MS and LC-MS/MS for small molecules and protein characterization, Protein characterization and identification by bottom up and top down proteomic approaches.