2-Phenylimidazo[1,2-a]pyridine-containing ligands of the 18-kDa translocator protein (TSPO) behave as agonists and antagonists of steroidogenesis in a mouse leydig tumor cell line

Midzak, Andrew; Denora, Nunzio; Laquintana, Valentino; Cutrignelli, Annalisa; Lopedota, Angela; Franco, Massimo; Altomare, Cosimo; Papadopoulos, Vassilios

doi:10.1016/j.ejps.2015.05.021

Cited by 17 publications

(14 citation statements)

References 25 publications

(40 reference statements)

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“…andg eneralized anxiety disorder (NCT00108836). [11,12] Since the identification of TSPO by meanso ft he benzodiazepines diazepam and Ro5-4864 (1) ( Figure 1), [13] structurally differentc lasses of highly potent and selective TSPO ligands have been reported, [14] including the isoquinolinecarboxamides,o fw hicht he 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-1-isoquinolinecarboxamide (PK11195, 2,F igure 1) is widely considered as aprototypical TSPO ligand, [15] imidazopyridines (alpidem), [16] indoleacetamides (FGIN-1-27), [17] aryloxyanilides, [18] 4-phenylquinazolines, [19,20] and purineacetamides (XBD173, also called AC-5216 13;see below). [11,12] In this context,w ed isclosed ac lass of potent and selective TSPO ligands, the N,N-dialkyl-2-phenylindol-3-ylglyoxylamides (PIGAs, 3-12,F igure 1), the majority of whichs howed K i values in the nanomolar/sub-nanomolar range;m oreover,anumber of compounds were able to effectively stimulate steroid biosynthesis.…”

Section: Nct00502515)mentioning

confidence: 99%

Residence Time, a New parameter to Predict Neurosteroidogenic Efficacy of Translocator Protein (TSPO) Ligands: the Case Study of N,N‐Dialkyl‐2‐arylindol‐3‐ylglyoxylamides

et al. 2017

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Neuroactive steroids are endogenousn euromodulators that, by binding to membrane receptors and tuning gene expression via intracellular receptors, regulate many physiological functions. They can be synthesized in the brain de novo, so that they are termedn eurosteroids, or reach the central nervous system (CNS) from peripheral steroidogenico rgans,s uch as adrenals and gonads, and are locally metabolized. Neurosteroid levels are alteredi ns everal psychiatric and neurodegenerative diseases as ac onsequence of an impairment of neurosteroidogenesis;b oth preclinical and clinical studies emphasize atherapeutic potentialofn euroactive steroids for these diseases, whereby symptomatology ameliorates upon restoration of neuroactive steroid concentrations. [1][2][3] Neuroactive steroids exert potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly acting as positive allosteric modulators at specific sites on the a-subunit of the g-aminobutyric acid type Ar eceptor (GABA A R).[4] In addition, neuroactive steroids exert neuroprotective, neurotrophic, anti-inflammatory and anti-apoptotic activitiesi ns everala nimal modelso ft raumatic brain and spinal cord injury,c erebral ischemia, peripheraln europathy,a nd neurodegeneratived iseases (e.g.,A lzheimer's and Parkinson's diseases,m ultiple sclerosis, etc.). [2] However,d irect administration of neuroactive steroids has several challenges, including short half-life,l ow bioavailability, poor aqueouss olubility,d evelopmento ft olerance, and undesired side effects such as sedationa nd memory impairment that limit their therapeutic use. Consequently,m odulation of neurosteroidogenesis to restoret he alterede ndogenous neuroactive steroidt one may be ab etter therapeutic approach. [1][2][3] The neuroactive steroidb iosynthetic pathway may be targeted at variousl evels in order to promote neurosteroidogenesis, [3] including the 18 kDat ranslocator protein (TSPO), an outer mitochondrial membrane protein expressed at high levels in peripheral and CNS steroid-producing cells.[5] TSPO plays ak ey role in the rate-limiting step of neuroactive steroid synthesis, consistingo fc holesterol translocation into mitochondria in order to supply it to the cytochrome P450 enzyme CYP11A1 for conversion into pregnenolone, the precursor of all neurosteroids. [6] Numerous TSPO ligandsa re able to potently and dose-dependently stimulate steroid biosynthesis in steroidogenic cells, and they have been proposed as innovative therapeutic tools in several pathological conditions, due to their neuroprotective, anxiolytic, anti-inflammatory,a nd regenerating properties in different in vitro andi nvivo models. [7][8][9][10] To date, phase II clinicalt rials have been concluded for the treatment of diabetic peripheral neuropathy (ClinicalTrials.gov identifier:Ta rgeting the biosyntheticp athway of neuroactive steroids with specific 18 kDa translocator protein (TSPO) ligandsm ay be av iable therapeutic approachf or av ariety of neurodegenerativea nd neuropsychiatri...

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Section: Nct00502515)mentioning

confidence: 99%

Residence Time, a New parameter to Predict Neurosteroidogenic Efficacy of Translocator Protein (TSPO) Ligands: the Case Study of N,N‐Dialkyl‐2‐arylindol‐3‐ylglyoxylamides

et al. 2017

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“…1,2,10,30,31 Exposure of steroidogenic cells and of mitochondria of steroidogenic cells to TSPO ligands, at concentrations close to their binding affinities, was found to stimulate steroid synthesis 1,31,32 ; furthermore, compounds that blocked TSPO action blocked hormone-induced steroid formation in cells and in vitro and in vivo. [33][34][35][36] TSPO was shown to be a high-affinity cholesterol binding protein, with cholesterol affinity localised to the C-terminal end of transmembrane helix 5 at a conserved cholesterol recognition amino acid consensus (CRAC) domain. 5,37 Mutations of particular amino acids of the CRAC domain were shown to eliminate the ability of TSPO to bind cholesterol.…”

Section: Structure and Function Of Tspo In Steroid Hormone Biosynthmentioning

confidence: 99%

Translocator protein (18 kDa): an update on its function in steroidogenesis

Papadopoulos

Fan

Zirkin

2018

J Neuroendocrinology

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about the role of this protein in steroid and heme synthesis. We review the data on the structure and function of TSPO, as well as the recent results obtained using various genetic animal models. Taken together, these studies suggest that TSPO is a unique mitochondrial pharmacological target for diseases that involve increased mitochondrial activity, including steroidogenesis. Although there is no known mammalian species that lacks TSPO, it is likely that, because of the importance of this ancient protein in evolution and mitochondrial function, redundant mechanisms may exist to replace it under circumstances when it is removed. K E Y W O R D Smitochondria, neuroactive steroids, steroids, translocator protein

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“…The number of structurally diverse TSPO drug ligands studied has increased over time, underlining the great attention of the scientific community in understanding the functions of this translocator protein in normal and pathological conditions. Extensive investigations proved that these ligands can affect steroidogenesis and in a range of concentrations can be considered pro‐apoptotic molecules potentially helpful for the treatment of tumors . Furthermore, recently various approaches have been proposed to visualize activated microglia using fluorescent probes chemically linked to TSPO ligands, and in addition, novel PET imaging probes to monitor the TSPO expression in pathological disorder such as neuroinflammation and cancers .…”

Section: Introductionmentioning

confidence: 99%

Bridging Pharmaceutical Chemistry with Drug and Nanoparticle Targeting to Investigate the Role of the 18‐kDa Translocator Protein TSPO

et al. 2017

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An interesting mitochondrial biomarker is the 18‐kDa mitochondrial translocator protein (TSPO). Decades of study have shown that this protein plays an important role in a wide range of cellular functions, including opening of the mitochondrial permeability transition pore as well as programmed cell death and proliferation. Variations in TSPO expression have been correlated to different diseases, from tumors to endocrine and neurological disorders. TSPO has therefore become an appealing target for both early diagnosis and selective mitochondrial drug delivery. The number of structurally different TSPO ligands examined has increased over time, highlighting the scientific community′s growing understanding of the roles of TSPO in normal and pathological conditions. However, only few TSPO ligands are characterized by the presence of groups that are potentially derivatizable; therefore only few such ligands are well suited for the preparation of targeted prodrugs or nanocarriers able to deliver therapeutics and/or diagnostic agents to mitochondria. This review provides an overview of the very few examples of drug delivery systems characterized by moieties that target TSPO.

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2-Phenylimidazo[1,2-a]pyridine-containing ligands of the 18-kDa translocator protein (TSPO) behave as agonists and antagonists of steroidogenesis in a mouse leydig tumor cell line

Cited by 17 publications

References 25 publications

Residence Time, a New parameter to Predict Neurosteroidogenic Efficacy of Translocator Protein (TSPO) Ligands: the Case Study of N,N‐Dialkyl‐2‐arylindol‐3‐ylglyoxylamides

Residence Time, a New parameter to Predict Neurosteroidogenic Efficacy of Translocator Protein (TSPO) Ligands: the Case Study of N,N‐Dialkyl‐2‐arylindol‐3‐ylglyoxylamides

Translocator protein (18 kDa): an update on its function in steroidogenesis

Bridging Pharmaceutical Chemistry with Drug and Nanoparticle Targeting to Investigate the Role of the 18‐kDa Translocator Protein TSPO

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