Peripheral benzodiazepine receptors

Synthesis of imidazo[l,2-d]pyridazines and their interaction with central and peripheral-type (mitochondrial) benzodiazepine receptors 98JHC1205. 

Joseph-Iiauzun, E., Farges, R., Delmas, P., Ferrara, P. Loison, G. (1997). The Mr 18,000 subunit of the peripheral-type benzodiazepine receptor exhibits both benzodiazepine and isoquinoline carboxamide binding sites in the absence of the voltage-dependent anion channel or of the adenine nucleotide carrier. J. Biol. Chem. 272, 28102-6. 

Norenberg MD, Itzhak Y, Bender S The peripheral benzodiazepine receptor and neurosteroids in hepatic encephalopathy. Adv Exp Med Biol 1997 420 95-111. 

Zanoli P, Giacobazzi A, Vaccari G, Zeneroli ML, Baraldi M Up-regulation of peripheral benzodiazepine receptors in brain areas of rats with galactosamine-induced hepatic encephalopathy in Bengtsson F, Jeppson B (eds) Progress in Hepatic Encephalopathy. Miami, CRC Press, 1991, pp 161-168. 

Lavoie J, Pomier Layrargues G, Butterworth RF Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy. Hepatology 1990 11 874-882. 

Belanger, M., Ahboucha, S., Desjardins, P. and Butterworth, R.F. Upregulation of peripheral-type (mitochondrial) benzodiazepine receptors in hyperammonemic syndromes consequences for neuronal excitability. Adv. Mol. Cell Biol. 31 983-997,2004. 

Several different changes in mitochondria occur during apoptosis. These include a change in membrane potential (usually depolarization), increased production of reactive oxygen species, potassium channel activation, calcium ion uptake, increased membrane permeability and release of cytochrome c and apoptosis inducing factor (AIF) [25]. Increased permeability of the mitochondrial membranes is a pivotal event in apoptosis and appears to result from the formation of pores in the membrane the proteins that form such permeability transition pores (PTP) may include a voltage-dependent anion channel (VDAC), the adenine nucleotide translocator, cyclophilin D, the peripheral benzodiazepine receptor, hexokinase and... 

PAF platelet-activating factor PTBR peripheral-type benzodiazepine receptor... 

Several intramolecular Heck reactions involve aryl halides cyclizing onto indole rings. Grigg first described the simple Heck cyclizations of 254 and 255 [270], and this was followed by similar Heck reactions reported by Kozikowski and Ma on the bromide corresponding to 254 and the IV-benzylindole 256 [271,272]. These investigators also observed cyclization to the C-3 position in a Heck reaction of indole 257, and they prepared a series of peripheral-type benzodiazepine receptors 258 using this chemistry. For example, 258 (n = 3, R = n-Pr) is obtained in 81% yield. 

Amri H, Ogwuegbu SO, Boujrad N, Drieu K, Papadopoulos V. (1996). In vivo regulation of peripheral-type benzodiazepine receptor and glucocorticoid synthesis by Ginkgo biloba extract EGb 761 and isolated ginkgolides. Endocrinology. 137(12) 5707-18. 

Papadopouios V, Widmaier EP, Amri H, Ziiz A, Li H, Culty M, Castello R, Philip GH, Sridaran R, Drieu K. (1998). In vivo studies on the roie of the peripheral benzodiazepine receptor (PBR) in steroidogenesis. Endocr Res. 124(3-4) 479-87. 

The activity of benzodiazepines may be terminated when the drug is removed from the benzodiazepine receptor site and diffuses into peripheral adipose tissue sites and then metabolized in the liver, or when there is a decrease in the sensitivity of the benzodiazepine receptors following chronic exposure to the drug (termed acute tolerance). The rate of development of acute tolerance appears to vary with the different benzodiazepines, making it difficult to relate the changes in therapeutic response to the changes in plasma concentration. 

Diazepinomicin (ECO-4601) (191) Dibenzo- diazepine alkaloid Diazepinomicin (ECO-4601) (191) Oncology RAS-mitogen-activated phosphokinase (MAPK) pathway inhibitor and inhibition of tiie peripheral benzodiazepine receptor Phase I/II Thallion (Ecopia) 906-910... 

Gourdeau H, McAlpine JB, Ranger M, Simard B, Berger F, Beaudry F, Falardeau P. (2008) Identification, characterization and potent antitumor activity of ECO-4601, a novel peripheral benzodiazepine receptor ligand. Cancer Chemother Pharmacol 61 911-921. 

A recent study found that cortical peripheral benzodiazepine receptors, as assessed with PET and [ C]PK11195, were increased by 30-40% in patients with AD when compared with healthy controls. This suggests active inflammatory processes in AD since PK11195 binds to activated microglia [72]. Several F-labeled tracers of the peripheral benzodiazepine receptor have been developed, and [i8p]PK14105 [73] and [i8p]FEDAA1106 [74] are the most well characterized. However, no reports have been published on the use of either of the two radiotracers in AD. The molecular structures of F-labeled tracers for the peripheral benzodiazepine receptor are shown in Fig. 5. 

M.-R. Zhang, J. Maeda, M. Ogawa, J. Noguchi, T. Ito, Y. Yoshida, T. Okauchi, S. Obayashi, T. Suhara, K. Suzuki, Development of a new radioligand, A/-(5-fluoro-2-phenoxyphenyl)-A/-(2[ F]fluoroethyl-5-methoxybenzyl)acetamide, for PET imaging of peripheral benzodiazepine receptor in primate brain, J. Med. Chem. 47 (2004) 2228-2235. 

Alpidem. Alpidem is an imidazopyridine partial agonist that also shows relative selectivity for the type I benzodiazepine receptor. Studies have shown an anxiolytic effect comparable with the classic benzodiazepines, but with an improved adverse effect profile [Pancheri et al. 1993). It has also been compared with buspirone in patients with generalized anxiety disorder and shown to be more rapidly effective and again to have a more favorable adverse effect profile [Legris et al. 1993). Longer-term studies with alpidem have shown that tolerance does not occur, and no significant problems of withdrawal on discontinuation were found [Chevalier et al. 1993). Alpidem was licensed in France for the treatment of anxiety but has now been suspended because of recent reports of alpidem-induced hepatic dysfunction. The reason for this is unclear, but it may be a reflection of the fact that alpidem also binds to peripheral benzodiazepine receptors, which are present in high density in the liver. 

Drugan RC, Philip HV Central and peripheral benzodiazepine receptors involvement in an organism s response to physical and psychological stress. Neurosci BehavRev 15 277, 1991... 

Pyrrolo[3,4-, ]pyridine derivatives, 147, have been prepared for comparison to the activity of alpidem, an anxiolytic imidazopyridine <1996JME4275>. The reduced derivative shows a significant affinity for the central benzodiazepine receptor. In contrast, the a,/3-unsaturated derivative shows significant affinity for the peripheral benzodiazepine receptor. 

---