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

Abstract

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.

Pemphigus vulgaris antibodies target the mitochondrial nicotinic acetylcholine receptors that protect keratinocytes from apoptolysis

“…Apparently, binding of autoantibody alters the conformational structure of the targeted mt-nAChR, which, in turn, induces changes of activity/structure of the associated mPTP proteins voltage-dependent anion channel, cyclophilin D, translocator protein (formerly peripheral benzodiazepine receptor) and/or adenine nucleotide translocase [37,38]. The mPTP opening causes massive swelling of mitochondria, rupture of outer membrane and release of intermembrane components, such as CytC, that induce formation of the apoptosome -a multimeric complex formed by Apaf-1 and procaspase-9 providing for activation of caspase-9.…”

Deepening the Topology of the Translocator Protein Binding Site by Novel N,N-Dialkyl-2-arylindol-3-ylglyoxylamides

“…Interestingly, the amide branches accommodate in a similar region with respect to the amide branches of the PK11195 (Supporting Information Figure S3), and we already demonstrated in our previous works that bulkier substituents are well tolerated in this region. 5,21,22,24,26,27,35 Different from the naphthyl series (29−35), the biphenyl one seems to be affected by the presence of bulkier substituents on the amide branch of the glyoxylamide moiety (26 vs 27, 28). This effect can be explained by the different bulkiness and shape of the biphenyl moiety with respect to the naphthyl one (Figure 1b−d and Supporting Information Figure S5), which in turn does not tolerate bulkier substituents on the amide group.…”

Targeting the 18-kDa translocator protein: recent perspectives for neuroprotection

“…Moreover, TSPO level changes have been reported in several human disorders, mainly in cancer, psychiatric and neurological diseases [14,15]. In this light, a number of structurally different classes of ligands targeting TSPO have been identified, as potential diagnostic or therapeutic agents, including the benzodiazepines 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (Ro5-4864) and diazepam, isoquinolinecarboxamides (PK-11195), dihydro-9H-purinacetamides (emapunil, XBD173), benzoxazines (etifoxine), vinca alkaloids (vinpocetine), pyrazolopyrimidines (DPA-713, DPA-714 and propargyl-DPA), sterols (olesoxime, TRO19622), indoleacetamides (SSR-180575) and others [16][17][18] (Figure 1). …”