Structural and electronic analysis of peripheral benzodiazepine ligands: Description of the pharmacophoric elements for their receptors

Georges, Guy; Vercauteren, Daniel P.; Vanderveken, D. J.; Horion, Rudi; Evrard, G.; Fripiat, J. J.; André, Jean‐Marie; Durant, François

doi:10.1002/qua.560381705

Cited by 15 publications

(27 citation statements)

References 41 publications

(6 reference statements)

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“…In these mapping studies, one of the most striking problem is the determination of the ligand conformation bound to the receptor (bioactive conformation). The (3) shows at least one important degree of conformational freedom [100]. These two ligands are supposed to bind non identical binding domains, as they have been reported to have different binding modalities [8,9].…”

Section: Isoquinolinecarboxamide Derivativesmentioning

confidence: 99%

Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands

Taliani

Pugliesi²,

Settimo

2011

CTMC

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The (18 kDa) Translocator Protein (TSPO), was initially identified in 1977 as peripheral binding site for the benzodiazepine diazepam and named "Peripheral-type benzodiazepine receptor (PBR)". It is an evolutionarily well-conserved protein particularly located at the outer/inner mitochondrial membrane contact sites, in closely association with the 32 kDa voltage-dependent anion channel (VDAC) and the 30 kDa adenine nucleotide translocase (ANT), thus forming the mitochondrial permeability transition pore (MPTP). TSPO is ubiquitary expressed in peripheral tissues (steroid producing tissues, liver, heart, kidney, lung, immune system) and in lower levels in the central nervous system, where it is mainly located in glial cells, and in neurons. TSPO is involved in a variety of biological processes such as cholesterol transport, steroidogenesis, calcium homeostasis, lipid metabolism, mitochondrial oxidation, cell growth and differentiation, apoptosis induction, and regulation of immune functions. In the last decade, many studies have reported that TSPO basal expression is altered in a number of human pathologies, such as cancer and neurodegenerative disorders (Huntington's and Alzheimer's diseases), as well as in various forms of brain injury and inflammation and anxiety. Consequently, TSPO has not only been suggested as a promising drug target for a number of therapeutic applications (anticonvulsant, anxiolytic, immunomodulating, etc.), but also as valid diagnostic marker for related-disease state and progression, prompting the development of specific labelled ligands as powerful tools for imaging techniques. A number of structurally different classes of ligands have been reported, showing high affinity and selectivity towards TSPO. Indeed, most of these ligands have been designed starting from selective CBR ligands which were structurally modified in order to shift their affinity towards TSPO. Extensive structure-activity relationship studies were performed allowing to hypothesize various TSPO pharmacophore models. The purpose of this paper is to highlight the structural requirements needed to obtain TSPO ligands with high affinity and selectivity.

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Section: Isoquinolinecarboxamide Derivativesmentioning

confidence: 99%

Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands

Taliani

Pugliesi²,

Settimo

2011

CTMC

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“…* * For molecular systems, the properties of which were computed in the RHF and UHF versions (Tables I-III), the UHF formalism is applied in the given case. * * * Data for (4-CH 3 Consequtive exclusion from consideration of the results of quantum chemical computations and experiments on the above molecules' dipole moments leads to the considerable increase in correlation coefficient r and narrowed confidence limits about the slope. Therewith the b value in the equation µ exper = bµ theor becames progressively closer to unity.…”

Section: Resultsmentioning

confidence: 98%

Thermodynamic Properties and Molecular Dipole Moments of Antimony Compounds from Quantum Chemical Evaluations

Pankratov

Uchaeva

2002

Phosphorus, Sulfur, and Silicon and the Related Elements

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By the PM3 method, standard values of entropy, heats and Gibbs energies of formation and dipole moments of the molecules have been computed for a series of inorganic and organic antimony compounds.Linear dependences P exper = bP theor (where P is any of the mentioned properties) have been stated, allowing a priori evaluation of thermodynamic characteristics and molecular dipole moments of Sb-containing substances. It has been concluded that triphenylstibinedichloride in benzene solution, as well as triphenylstibinehydroxychloride in dioxane medium, exist in the form of trigonal bipyramid with two axial chlorine and oxygen atoms.

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“…In the early stages of this work, some SAR data about 2 and related compounds were reported . Georges and co-workers carried out molecular orbital calculations on a group of 2 congeners in order to map the TSPO binding site . At that time, human, bovine, rat, and murine TSPO were isolated, sequenced, and cloned, and secondary and tertiary structural models of the of the TSPO were reported as well.…”

Section: Tspo Medicinal Chemistry Contributed By Our Groupmentioning

confidence: 99%

“…Moreover, 26b , which is characterized by dihedral angle ψ = 50°, displayed an affinity comparable to that of 26a . Therefore, the constraint of the conjugated phenyl ring failed to reveal a preferred conformation for the interaction with TSPO binding site, in agreement with the hypothesis of Georges et al …”

Section: Tspo Medicinal Chemistry Contributed By Our Groupmentioning

confidence: 99%

“…69 Georges and co-workers carried out molecular orbital calculations on a group of 2 congeners in order to map the TSPO binding site. 96 At that time, human, bovine, rat, and murine TSPO were isolated, sequenced, and cloned, 97 and secondary and tertiary structural models of the of the TSPO were reported as well. These models consisted in a transmembrane region (five α-helices comprising 21 hydrophobic residues that are connected by loops rich in hydrophilic residues) showing the N-terminus in the mitochondrial domain and the C-terminus exposed to the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

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Exploring Translocator Protein (TSPO) Medicinal Chemistry: An Approach for Targeting Radionuclides and Boron Atoms to Mitochondria

Giordani¹,

Menziani

Moresco

et al. 2021

J. Med. Chem.

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Translocator protein 18 kDa [TSPO or peripheraltype benzodiazepine receptor (PBR)] was identified in the search of binding sites for benzodiazepine anxiolytic drugs in peripheral regions. In these areas, binding sites for TSPO ligands were recognized in steroid-producing tissues. TSPO plays an important role in many cellular functions, and its coding sequence is highly conserved across species. TSPO is located predominantly on the membrane of mitochondria and is overexpressed in several solid cancers. TSPO basal expression in the CNS is low, but it becomes high in neurodegenerative conditions. Thus, TSPO constitutes not only as an outstanding drug target but also as a valuable marker for the diagnosis of a number of diseases. The aim of the present article is to show the lesson we have learned from our activity in TSPO medicinal chemistry and in approaching the targeted delivery to mitochondria by means of TSPO ligands.

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Structural and electronic analysis of peripheral benzodiazepine ligands: Description of the pharmacophoric elements for their receptors

Cited by 15 publications

References 41 publications

Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands

Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands

Thermodynamic Properties and Molecular Dipole Moments of Antimony Compounds from Quantum Chemical Evaluations

Exploring Translocator Protein (TSPO) Medicinal Chemistry: An Approach for Targeting Radionuclides and Boron Atoms to Mitochondria

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