Benzodiazepine Receptor Ligands Research Articles

Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicity

The peripheral-type benzodiazepine receptor (PBR) is a critical component of the mitochondrial permeability transition pore, which is involved in the regulation of cell survival. Different forms of brain injury result in induction of the expression of the PBR in the areas of neurodegeneration, mainly in reactive glial cells. The consequences of induction of PBR expression after brain injury are unknown. To test whether PBR may be involved in the regulation of neuronal survival after injury, we have assessed the effect of two PBR ligands, Ro5-4864 and PK11195, on neuronal loss induced by kainic acid in the hippocampus. Systemic administration of kainic acid to male rats resulted in the induction of a reactive phenotype in astrocytes and microglia and in a significant loss of hilar neurons in the dentate gyrus. Administration of Ro5-4864, before the injection of kainic acid, decreased reactive gliosis in the hilus and prevented hilar neuronal loss. In contrast, PK11195 was unable to reduce reactive gliosis and did not protect hilar neurons from kainic acid. These findings suggest that the PBR is involved in control of neuronal survival and gliosis after brain injury and identify this molecule as a potential target for neuroprotective interventions.

11C]Vinpocetine: a prospective peripheral benzodiazepine receptor ligand for primate PET studies

Vinpocetine, a synthetic derivative of the Vinca minor alkaloid vincamine, is a widely used drug in neurological practice. We tested the hypothesis that vinpocetine binds to peripheral benzodiazepine binding sites (PBBS) and is therefore a potential ligand of PBBS. Positron emission tomography (PET) measurements in two cynomolgous monkeys showed that pretreatment with vinpocetine markedly reduced the brain uptake of [ 11C]PK11195, a known PBBS radioligand. On the other hand, whereas pretreatment with PK11195 increased the brain uptake of [ 11C]vinpocetine due to the blockade of PBBS in the periphery, it significantly reduced the binding potential (BP) values of [ 11C]vinpocetine in the whole brain and in individual brain structures to PK11195. These findings indicate that, whereas the two ligands have different affinities to PBBS, vinpocetine is a potent ligand of PBBS, which in turn suggests that the pharmacological activity of vinpocetine may involve the regulation of glial functions.

Unraveling biologic therapy for Bcl-2-expressing malignancies

Cancer cells that express excessive levels of Bcl-2 pose a major problem in the delivery of curative therapy. Most treatments for such cancer involve chemotherapy to induce the apoptotic process. While these therapies often result in disease control for periods of time, failure to initiate apoptosis as a result of acquired resistance limits the effectiveness of treatment for many common hematopoietic and solid malignancies, and ultimately death from the malignancy still occurs. Various anti-apoptotic proteins of the Bcl-2 family that localize to the mitochondria appear to be involved in this resistance mechanism. However, recent advances in the understanding of malignant cell biology, achieved through both genomics and proteomics, have made it possible to explore novel approaches directed at re-establishing sensitivity to chemotherapy, presenting an attractive strategy for cancer treatment. In this article we discuss how this may be achieved by lowering Bcl-2 anti-apoptotic protein expression using antisense oligonucleotides or, alternatively, by functionally antagonizing Bcl-2 using ligands of the mitochondrial benzodiazepine receptor.

Novel lipoidal derivatives of pregnenolone and dehydroepiandrosterone and absence of their sulfated counterparts in rodent brain

A new sample preparation method coupled to GC-MS analysis was developed and validated for quantification of sulfate esters of pregnenolone (PREG-S) and dehydroepiandrosterone (DHEA-S) in rat brain. Using a solid-phase extraction recycling protocol, the results show that little or no PREG-S and DHEA-S (<1 pmol/g) is present in rat and mouse brain. These data are in agreement with studies in which steroid sulfates were analyzed without deconjugation. We suggest that the discrepancies between analyses with and without deconjugation are caused by internal contamination of brain extract fractions, supposed to contain steroid sulfates, by lipoidal forms of PREG and DHEA (L-PREG and L-DHEA, respectively). These derivatives can be acylated very efficiently with heptafluorobutyric anhydride and triethylamine, and their levels in rodent brain (approximately 1 nmol/g) are much higher than those of their unconjugated counterparts. They are distinct from fatty acid esters, and preliminary data do not favor structures such as sulfolipids or sterol peroxides. Noncovalent interactions between steroids and proteolipidic elements, such as lipoproteins, could account for some experimental data. Given their abundance in rodent brain, the structural characterization and biological functions of L-PREG and L-DHEA in the central nervous system merit considerable attention.

Increased Brain Concentrations of Endogenous (Non-benzodiazepine) GABA-A Receptor Ligands in Human Hepatic Encephalopathy

It has been suggested that alterations of GABAergic neurotransmission are implicated in the pathophysiology of hepatic encephalopathy (HE). Increased concentrations of endogenous benzodiazepines with positive allosteric modulatory properties at the GABA-A receptor complex were proposed as a pathophysiological mechanism to explain increased GABAergic tone in HE. However, results of controlled trials with benzodiazepine receptor antagonists have yielded equivocal results and increases in benzodiazepine levels in body fluids of cirrhotic patients were suggested to be largely accounted for by previous pharmaceutical benzodiazepine intake. In the present study the issue of benzodiazepine receptor ligands in brains of cirrhotic patients, and their contribution to alterations of GABA-A receptor complex in HE are addressed. "Benzodiazepine-like" ligands were present in trace amounts in autopsied brain tissue from control subjects (0.2 +/- 0.2 ng/g tissue), and from cirrhotic patients not previously exposed to benzodiazepine medication (0.8 +/- 0.4 ng/g tissue). In contrast, these ligands accumulate in brain extracts from cirrhotic patients previously exposed to benzodiazepines by up to 200-fold (161.5 +/- 93.2 DE ng/g tissue). Brain extracts from cirrhotic patients increased the binding of the GABA-A receptor agonist [3H]muscimol. This increase was minimal with brain extracts from controls (6.8 +/- 2.8%), but was significant with brain extracts from cirrhotic patients without (29.4 +/- 2.7%), or with (55.1 +/- 7.6%) previous exposure to benzodiazepines. Addition of flumazenil, a selective benzodiazepine receptor antagonist did not significantly modify the increase of [3H]muscimol binding by brain extracts from patients without prior exposure to benzodiazepines and only partially inhibited the increase of [3H]muscimol binding in presence of brain extracts from cirrhotic patients previously exposed to benzodiazepines. These findings suggest the presence of nonbenzodiazepine substances (possibly neurosteroids) with positive allosteric modulatory properties at the GABA-A receptor complex in brain in hepatic encephalopathy.

Evaluation of a radiolabelled peripheral benzodiazepine receptor ligand in the central nervous system inflammation of experimental autoimmune encephalomyelitis: a possible probe for imaging multiple sclerosis

Peripheral benzodiazepine receptors (PBRs) are upregulated on macrophages and activated microglia, and radioligands for the PBRs can be used to detect in vivo neuroinflammatory changes in a variety of neurological insults, including multiple sclerosis. Substituted 2-phenyl imidazopyridine-3-acetamides with high affinity and selectivity for PBRs have been prepared that are suitable for radiolabelling with a number of positron emission tomography and single-photon emission computed tomography (SPECT) isotopes. In this investigation, the newly developed high-affinity PBR ligand 6-chloro-2-(4'-iodophenyl)-3-(N,N-diethyl)imidazo[1,2-a]pyridine-3-acetamide, or CLINDE, was radiolabelled with 123I and its biodistribution in the central nervous system (CNS) of rats with experimental autoimmune encephalomyelitis (EAE) evaluated. EAE was induced in male Lewis rats by injection of an emulsion of myelin basic protein and incomplete Freund's adjuvant containing Mycobacterium butyricum. Biodistribution studies with 123I-CLINDE were undertaken on EAE rats exhibiting different clinical disease severity and compared with results in controls. Disease severity was confirmed by histopathology in the spinal cord of rats. The relationship between inflammatory lesions and PBR ligand binding was investigated using ex vivo autoradiography and immunohistochemistry on rats with various clinical scores. 123I-CLINDE uptake was enhanced in the CNS of all rats exhibiting EAE when compared to controls. Binding reflected the ascending nature of EAE inflammation, with lumbar/sacral cord>thoracic cord>cervical cord>medulla. The amount of ligand binding also reflected the clinical severity of disease. Ex vivo autoradiography and immunohistochemistry revealed a good spatial correspondence between radioligand signal and foci of inflammation and in particular ED-1+ cells representing macrophages and microglia. These results demonstrate the ability of 123I-CLINDE to measure in vivo inflammatory events represented by increased density of PBRs and suggest that 123I-CLINDE warrants further investigation as a potential SPECT marker for imaging of CNS inflammation.

Cell cycle-related signaling pathways modulated by peripheral benzodiazepine receptor ligands in colorectal cancer cells

Specific ligands of the peripheral benzodiazepine receptor (PBR) have been shown to induce both apoptosis and G1/G0 cell cycle arrest in colorectal cancers. The signaling pathways leading to cell cycle arrest are still unknown. Using cDNA array technology, we identified signaling molecules involved in cell cycle arrest induced by the PBR ligands FGIN-1-27 and PK 11195. Differential gene expression was confirmed by semi-quantitative RT-PCR or Western blot analysis of gene products. The PBR ligand-mediated signaling involved the upregulation of the cyclin-dependent kinase inhibitors p21Waf1/CIP1 and p27Kip1, cdc16, and the cell cycle inhibitors gadd45 and gadd153, the downregulation of the cyclins D1 and B1, as well as the inactivation of ERK1/2. The p21-deficient colorectal cancer cell line HCT116 p21−/− was significantly less sensitive to PBR ligands than the parental HCT116 wild-type cells, demonstrating the functional involvement of p21Waf1/CIP1 in PBR ligand-mediated G1 arrest. This study thus revealed PBR ligand-triggered signaling pathways leading to cell cycle arrest. Moreover, we showed the functional implication and interaction of differentially expressed gene products and provided a model of signaling pathways involved in PBR ligand-induced G1 arrest. These results form the basis for future PBR ligand-mediated therapeutic approaches.

Synthesis of Methylenedioxy‐Bearing 1‐Aryl‐3‐carboxylisoquinolines Using a Modified Ritter Reaction Procedure.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Quantitative evaluation of central-type benzodiazepine receptors with [125I] Iomazenil in experimental epileptogenesisI. The rat kainate model of temporal lobe epilepsy

This study aimed at quantitatively evaluating hippocampal central-type benzodiazepine receptors (BZRs) in the kainate model of temporal lobe epilepsy (TLE) by in vitro autoradiography (ARG) using [125I] Iomazenil (IMZ) specific ligand for central-type BZRs. Kainate (1 μg/0.5 μl) was injected into the left amygdala to induce limbic status epilepticus. One, three, or six months after injection, in vitro ARG with [125I] IMZ and cell counts were performed in the hippocampal CA1–4 regions and dentate gyrus ipsilateral to the kainate injection site, and were compared with the vehicle-injected control group. In all kainate-treated rats, clear pyramidal neuron loss was observed in left hippocampal areas CA1–4. Compared with the control group, progressive reduction of [125I] IMZ binding was also observed. This resulted in a marked binding decrease paralleling pyramidal neuron loss in hippocampal areas CA1 (down to 83% of control), CA2 (76%), CA3 (75%), and CA4 (90%) at 6 months after kainate administration. Conversely, [125I] IMZ binding significantly increased in the dentate gyrus (up to 106% of control) at 1 month, but returned to nearly normal at 3–6 months. These results suggest that central-type BZR neuroimaging is useful in detecting hippocampal sclerosis in the mesial TLE, though central BZR alterations differ depending on hippocampal subfields and post-seizure time-courses.

Quantitative evaluation of central-type benzodiazepine receptors with [ 125I] Iomazenil in experimental epileptogenesis : I. The rat kainate model of temporal lobe epilepsy

This study aimed at quantitatively evaluating hippocampal central-type benzodiazepine receptors (BZRs) in the kainate model of temporal lobe epilepsy (TLE) by in vitro autoradiography (ARG) using [ 125I] Iomazenil (IMZ) specific ligand for central-type BZRs. Kainate (1 μg/0.5 μl) was injected into the left amygdala to induce limbic status epilepticus. One, three, or six months after injection, in vitro ARG with [ 125I] IMZ and cell counts were performed in the hippocampal CA1–4 regions and dentate gyrus ipsilateral to the kainate injection site, and were compared with the vehicle-injected control group. In all kainate-treated rats, clear pyramidal neuron loss was observed in left hippocampal areas CA1–4. Compared with the control group, progressive reduction of [ 125I] IMZ binding was also observed. This resulted in a marked binding decrease paralleling pyramidal neuron loss in hippocampal areas CA1 (down to 83% of control), CA2 (76%), CA3 (75%), and CA4 (90%) at 6 months after kainate administration. Conversely, [ 125I] IMZ binding significantly increased in the dentate gyrus (up to 106% of control) at 1 month, but returned to nearly normal at 3–6 months. These results suggest that central-type BZR neuroimaging is useful in detecting hippocampal sclerosis in the mesial TLE, though central BZR alterations differ depending on hippocampal subfields and post-seizure time-courses.

Quantitative evaluation of central-type benzodiazepine receptors with [ 125I]Iomazenil in experimental epileptogenesis: II. The rat cortical dysplasia model

[ 123I]Iomazenil (IMZ) is a specific ligand for central-type benzodiazepine receptors (BZRs) and is available for single photon emission computed tomography (SPECT) to detect epileptogenic foci. We have recently demonstrated time-dependent alterations of [ 125I]IMZ binding in the rat kainate model of temporal lobe epilepsy [Tamagami, H., Morimoto, K., Watanabe, T., Ninomiya, T., Hirao, T., Tanaka, A., Kakumoto, M., 2004. Quantitative evaluation of central-type benzodiazepine receptors with [ 125I]Iomazenil in experimental epileptogenesis. I. The rat kainate model of temporal lobe epilepsy. Epilepsy Res. 61, 105–110.]. In the present study, we investigated regional changes in central-type BZRs in the cortical dysplasia (CD) model of epilepsy in rats. Pregnant rats were irradiated at day 17 of gestation with 1.2 Gy to produce CD in their pups, and in vitro autoradiography with [ 125I]IMZ was performed at 8 weeks after birth. Intact rats at the same age were used as controls. [ 125I]IMZ binding was significantly decreased in various cortical regions of the in utero irradiated rats, including the bilateral frontal cortex (down to 92–93% of control), cingulate cortex (91–92%), hippocampal areas CA1 (95%), CA2 (94–95%) and CA4 (95–96%), and caudate/putamen (90–94%). In addition, amygdala-kindling was significantly facilitated in the CD model, especially during the late phase of kindling, suggesting seizure susceptibility of this model. These results may replicate the clinical usefulness of central-type BZRs neuroimaging for detection of human epileptogenic CD and indicate dysfunction of GABA-A/BZR-mediated inhibition responsible for the seizure susceptibility.

Peripheral benzodiazepine receptor ligands induce apoptosis and cell cycle arrest in human hepatocellular carcinoma cells and enhance chemosensitivity to paclitaxel, docetaxel, doxorubicin and the Bcl–2 inhibitor HA14–1

Background/Aims: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths worldwide. Thus, novel therapies are urgently needed. A promising approach is the use of peripheral benzodiazepine receptor (PBR) ligands which have been shown to inhibit the proliferation of various tumors. There exist no functional studies of PBR in HCC

Cell cycle-related signaling pathways modulated by peripheral benzodiazepine receptor ligands in colorectal cancer cells

Cell cycle-related signaling pathways modulated by peripheral benzodiazepine receptor ligands in colorectal cancer cells

GABA A/central benzodiazepine receptor and peripheral benzodiazepine receptor ligands as inducers of phenobarbital-inducible CYP2B and CYP3A

A sequence critical for phenobarbital (PB) induction, the PB response unit (PBRU), situated upstream of the rat CYP2B1 and CYP2B2 genes, includes two nuclear receptor binding sites, NR1 and NR2. When NR1 and NR2 are mutated PB responsiveness is abolished. While no nuclear receptor for which PB is an agonist ligand has yet been identified, PB is a ligand of GABA A receptors and it can displace [ 3H] 1-(2-chlorophenyl)- N-methyl- N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11195) from its binding site on the peripheral benzodiazepine receptor (PBR). We assessed CYP2B levels in primary rat hepatocytes following treatment with 10 ligands of either or both of these receptors. All compounds tested were found to be CYP2B1/CYP2B2 inducers and most were CYP3A inducers. Five had not previously been described as CYP2B1/CYP2B2 inducers: bicuculline, flunitrazepam, 4′-chlorodiazepam (Ro5-4864), N, N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide (FGIN 1–27) and 7-(dimethylcarbamoyloxy)-6-phenylpyrrolo-[2,1- d][1,5]benzothiazepine (DCPPBT). Reporter gene analysis demonstrated that CYP2B induction by these agents and other PBR or GABA A receptor ligands is mediated through the PBRU and the NR1/NR2 sites, suggesting a molecular mechanism similar to that for PB induction. The potencies for PBRU-dependent induction by 11 ligands of PBR or the GABA A receptor was evaluated. FGIN-127, DCPPBT and PK 11195 exhibited EC 50 values for PBRU-dependent transcription activation about three orders of magnitude higher than the reported affinities of the PBR for these agents, arguing against the involvement of the PBR in PB induction. However the EC 50 values found for the agents tested encourage further investigation on the possible involvement of the GABA A receptor in PB induction.

Peripheral benzodiazepine receptor ligands induce apoptosis and cell cycle arrest in human hepatocellular carcinoma cells and enhance chemosensitivity to paclitaxel, docetaxel, doxorubicin and the Bcl-2 inhibitor HA14-1

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths worldwide. Thus, novel therapies are urgently needed. A promising approach is the use of peripheral benzodiazepine receptor (PBR) ligands which inhibit the proliferation of various tumors. PBR expression both in human HCC cell lines and in tumor specimens of HCC patients was analyzed by RT-PCR and immunostaining. To evaluate PBR ligands for the treatment of HCC, we tested their effects on human HCC cells. PBR was localized to the mitochondria both of HCC cell lines and tumor tissues of HCC patients. In contrast, normal liver did not express PBR. PBR ligands inhibited the proliferation of HCC cell lines by inducing apoptosis and cell cycle arrest. Apoptosis was characterized by a breakdown of the mitochondrial membrane potential, caspase-3 activation and nuclear degradation. Furthermore, pro-apoptotic Bax was overexpressed while anti-apoptotic Bcl-2 and Bcl-X(L) were suppressed. Cell cycle was arrested both at the G1/S- and G2/M-checkpoints. Synergistic anti-neoplastic effects were obtained by a combination of PBR ligands with cytostatic drugs (paclitaxel, docetaxel, doxorubicin), or with an experimental Bcl-2 inhibitor. This is the first report on the induction of apoptosis and cell cycle arrest by PBR ligands in HCC cells. Moreover, PBR ligands sensitized HCC cells to taxans and doxorubicin.

The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood-brain barrier and exhibits anticonvulsive effects.

The functional characterization of hispidulin (4',5,7-trihydroxy-6-methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity. After chemical synthesis, hispidulin was investigated at recombinant GABA(A)/BZD receptors expressed by Xenopus laevis oocytes. Concentrations of 50 nm and higher stimulated the GABA-induced chloride currents at tested receptor subtypes (alpha(1-3,5,6)beta(2)gamma(2)S) indicating positive allosteric properties. Maximal stimulation at alpha(1)beta(2)gamma(2)S was observed with 10 microm hispidulin. In contrast to diazepam, hispidulin modulated the alpha(6)beta(2)gamma(2)S-GABA(A) receptor subtype. When fed to seizure-prone Mongolian gerbils (Meriones unguiculatus) in a model of epilepsy, hispidulin (10 mg kg(-1) body weight (BW) per day) and diazepam (2 mg kg(-1) BW per day) markedly reduced the number of animals suffering from seizures after 7 days of treatment (30 and 25% of animals in the respective treatment groups, vs 80% in the vehicle group). Permeability across the blood-brain barrier for the chemically synthesized, (14)C-labelled hispidulin was confirmed by a rat in situ perfusion model. With an uptake rate (K(in)) of 1.14 ml min(-1) g(-1), measurements approached the values obtained with highly penetrating compounds such as diazepam. Experiments with Caco-2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 microm, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites.

Inhibition by miltirone of up-regulation of GABA A receptor α 4 subunit mRNA by ethanol withdrawal in hippocampal neurons

Miltirone, a tanshinone isolated from the root of Salvia miltiorrhiza, has been characterized as a low-affinity ligand for central benzodiazepine receptors. We have now shown that this compound bound with low affinity (micromolar range) to central benzodiazepine recognition sites but did not interact with peripheral benzodiazepine receptors. It failed to potentiate Cl − currents induced by γ-aminobutyric acid (GABA) both in Xenopus oocytes expressing recombinant human GABA A receptors and in cultured rat hippocampal pyramidal cells, but it inhibited the ability of diazepam to potentiate the effect of GABA in these systems. Miltirone (1–10 μM) also partially inhibited the increase in the abundance of the mRNA for the α 4 subunit of the GABA A receptor induced by ethanol withdrawal in cultured hippocampal neurons. These results suggest that miltirone might ameliorate the symptoms associated with discontinuation of long-term administration of ethanol or of other positive modulators of the GABA A receptor.

The peripheral benzodiazepine receptor ligand PK11195 overcomes different resistance mechanisms to sensitize AML cells to gemtuzumab ozogamicin

AbstractThe antibody-targeted therapeutic, gemtuzumab ozogamicin (GO, Mylotarg), is approved for treatment of relapsed acute myeloid leukemia (AML). We previously showed that AML blasts from GO refractory patients frequently express the drug transporters P-glycoprotein (Pgp) and/or multidrug resistance protein (MRP). We also previously reported that inhibition of drug transport by the Pgp modulator, cyclosporine A (CSA), can increase GO sensitivity in Pgp+ AML cells and that the peripheral benzodiazepine receptor ligand, PK11195, sensitizes AML cells to standard chemotherapeutics both by inhibiting Pgp-mediated efflux and by promoting mitochondrial apoptosis. We now show that PK11195 also can overcome multiple resistance mechanisms to increase GO sensitivity in AML cells, including resistance associated with expression of drug transporters and/or antiapoptotic proteins. PK11195 substantially increases GO cytotoxicity in AML cells from many different cell lines and primary patient samples, often more effectively than CSA. We also show that PK11195 is nontoxic in NOD/SCID mice and can sensitize xenografted human AML cells to GO. Since PK11195 is well tolerated in humans as a single agent, its further study as a multifunctional chemosensitizer for anti-AML therapies, including GO-based therapies, is warranted. (Blood. 2004;103:4276-4284)

Synthesis of methylenedioxy-bearing 1-aryl-3-carboxylisoquinolines using a modified Ritter reaction procedure

This paper describes original approaches aimed at the preparation of electron-rich 1-aryl-3-carboxylisoquinolines. Our first attempt led to an efficient preparation of 1-hydroxyisoquinoline-3-carboxylic acid methyl ester starting from bromophthalide via a rearrangement of 2-acetylamino-2-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-malonic acid dimethyl ester. However, as its eventual application to the synthesis of methylenedioxy-bearing substrates seemed rather long, a second approach involving an extension of the Ritter reaction to safrole was devised. We thus report that, under proper experimental settings, the use of 54% tetrafluoroboric acid in ether enables a Ritter reaction between safrole and 3,4,5-trimethoxybenzonitrile yielding 17% of 7-methyl-5-(3,4,5-trimethoxyphenyl)-7,8-dihydro-[1,3]dioxolo[4,5- g]isoquinoline. This acidic reagent avoids the extensive decomposition seen when using the classical Ritter reaction conditions (i.e.: concentrated sulfuric acid). Further chemical transformations of this methyl-bearing dihydroisoquinoline led to the methylenedioxy-bearing 1-aryl-3-carboxylisoquinoline. These derivatives are related to the peripheral benzodiazepine receptor ligand PK 11195 as well as falcipain-2 inhibitors and other potential antitumor agents.

Design, synthesis, and structure–activity relationships of novel tetracyclic compounds as peripheral benzodiazepine receptor ligands

The peripheral benzodiazepine receptor (PBR) is pharmacologically distinct from the central benzodiazepine receptor (CBR) and has been identified in a wide range of peripheral tissues as well as in the central nervous system. Although numerous studies have been performed of it, the physiological roles and functions of the PBR are still unclear. In the present study, in exploring new types of ligands for PBR, we found that a new series of compounds having a tetracyclic ring system, which were designed from FGIN-1-27, exhibited high affinities for PBR. We prepared and evaluated them for PBR affinities. The results of binding tests showed that 12e and 12f were the most potent PBR ligands among them ( 12e: IC 50=0.44 nM, 12f: IC 50=0.37 nM). In this paper, we present the design, synthesis, and structure–activity relationships (SARs) of novel tetracyclic compounds.