2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) is an analog of the quinoxalinedione antagonists to the non-N-methyl-D-aspartate (non-NMDA) glutamate receptor. NBQX is a potent and selective inhibitor of binding to the quisqualate subtype of the glutamate receptor, with no activity at the NMDA and glycine sites. NBQX protects against global ischemia, even when administered 2 hours after an ischemic challenge.
1 The goal of this study was to characterize the agonist pharmacology of human 5-HT 2A , 5-HT 2B and 5-HT 2C (VSV) receptors expressed in CHO-K1 (Chinese hamster ovary) cells. 2 We used a¯uorometric imaging plate reader (FLIPR) which allows rapid detection of rises in intracellular calcium levels upon the addition of agonists. 5 Many agonists tested had partial agonist actions when compared to 5-HT, and a wide range of relative e cacies were exhibited, which was cell line dependent. For example, mCPP had a relative e cacy of 65% at 5-HT 2C receptors but 525% at either 5-HT 2A or 5-HT 2B receptors. 6 Interpretation of literature values of functional assays using di erent cell lines, di erent receptor expression levels and di erent receptor isoforms, is complex. Species di erences and the previous use of antagonist radioligands to characterize agonist potency in binding assays emphasizes the importance of studying agonists in the same experiment using the same assay conditions and parental cell lines.
Brain trauma is associated with acute functional impairment and neuronal injury. At present, it is unclear to what extent disturbances in ion homeostasis are involved in these changes. We used ion-selective microelectrodes to register interstitial potassium ([K+]e) and calcium ([Ca2+]e) concentrations in the brain cortex following cerebral compression contusion in the rat. The trauma was produced by dropping a 21 g weight from a height of 35 cm onto a piston that compressed the cortex 1.5 mm. Ion measurements were made in two different locations of the contused region: in the perimeter, i.e., the shear stress zone (region A), and in the center (region B). The trauma resulted in an immediate increase in [K+]e from a control level of 3 mM to a level > 60 mM in both regions, and a concomitant negative shift in DC potential. In both regions, there was a simultaneous, dramatic decrease in [Ca2+]e from a baseline of 1.1 mM to 0.3-0.1 mM. Interstitial [K+] and the DC potential normalized within 3 min after trauma. In region B, [Ca2+]e recovered to near control levels within 5 min after ictus. In region A, however, recovery of [Ca2+]e was significantly slower, with a return to near baseline values within 50 min after trauma. The prolonged lowering of [Ca2+]e in region A was associated with an inability to propagate cortical spreading depression, suggesting a profound functional disturbance. Histologic evaluation 72 h after trauma revealed that neuronal injury was confined exclusively to region A. The results indicate that compression contusion trauma produces a transient membrane depolarization associated with a pronounced cellular release of K+ and a massive Ca2+ entry into the intracellular compartment. We suggest that the acute functional impairment and the subsequent neuronal injury in region A is caused by the prolonged disturbance of cellular calcium homeostasis mediated by leaky membranes exposed to shear stress.
A series of novel 3-(3-substituted-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro- 1-methylpyridines (substituted-TZTP; 5a-l, 7a-h, 8, 9c-n, 11, 13j) were synthesized and tested for central muscarinic cholinergic receptor affinity by using [3H]-oxotremorine-M (Oxo-M) and [3H]-pirenzepine (Pz) as ligands. The potency and efficacy of the compounds for the pharmacological defined M1 and M2 muscarinic receptors were determined on isolated electrically stimulated rabbit vas deferens and on spontaneously beating isolated guinea pig atria, respectively. Selected compounds were also tested for M3 activity in the isolated guinea pig ileum. The C1-8 alkoxy-TZTP 5a-l analogues all displaced [3H]-Oxo-M and [3H]-Pz with low nanomolar affinity. Depicting chain length against Oxo-M binding and against Pz binding the unbranched C1-8 alkoxy-TZTP (5a-h) derivatives produced U-shaped curves with butoxy- (5d) and (pentyloxy)-TZTP (5e) as the optimum chain length, respectively. This U-shaped curve was also seen in the ability of the compounds 5a-h to inhibit the twitch height in the vas deferens preparation. The (pentyloxy)- (5e) and the (hexyloxy)-TZTP (5f) analogues produced an over 90% inhibition of the twitch height with IC50 values in the low picomolar range. In both the atria and in the ileum preparations 5f had low efficacy and potency. With the (alkylthio)-TZTP (7a-h) analogues the structure-activity relationship was similar to the one observed with the alkoxy (5a-h) analogues, but generally 7a-h had higher receptor affinity and was more potent than the corresponding 5a-h. However, the C3-8 alkyl-TZTP (9c,e,g,h) analogues had 10-100 times lower affinity for the central muscarinic receptors than the corresponding alkoxy and alkylthio derivatives, and their efficacy in the vas deferens preparation was too low to obtain IC50 values. The unsubstituted TZTP (11) compound was a potent but nonselective muscarinic agonist. The two 3-(3-butoxy/(hexyloxy)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahy dro-1- methylpyridines (butoxy/hexyloxy)-OZTP; 19a/b) were also synthesized and tested. Both 19a and 19b had much lower affinity for the central muscarinic receptors than 5d and 5f, and the efficacy of 19a,b was too low to give IC50 values in the vas deferens preparation. Therefore, the C5-6 (alkyloxy)/(alkylthio)-TZTP's represent a unique series of potent functional M1 selective muscarinic agonists.
Islet amyloidosis is characterized by the deposition and accumulation of amylin in pancreatic beta-cells and is observed in 90% of patients with type 2 diabetes. Previous studies have also revealed the presence of the specific heparan sulfate proteoglycan, perlecan, colocalized to islet amyloid deposits, similar to perlecan's known involvement with other amyloid proteins. In the present study, perlecan purified from the Engelbreth-Holm-Swarm (EHS) tumor was used to define perlecan's interactions with amylin (i.e., islet amyloid polypeptide) and its effects on amylin fibril formation. Using a solid phase-binding immunoassay, human amylin, but not rat amylin, bound immobilized EHS perlecan with a single dissociation constant (Kd) = 2.75 x 10(-6) mol/l. The binding of human amylin to perlecan was similarly observed using perlecan heparan sulfate glycosaminoglycans (GAGs), and was completely abolished by 10 micromol/l heparin. Using thioflavin T fluorometry, Congo red staining, and electron microscopy methodology, intact perlecan was found to enhance amylin fibril formation in a dosage-dependent manner, with the majority of these effects attributed to the heparan sulfate GAG chains of perlecan. Other sulfated GAGs and related macromolecules were also effective in the enhancement of amylin fibril formation in the order of heparin > heparan sulfate > chondroitin-4-sulfate = dermatan sulfate = dextran sulfate > pentosan polysulfate, implicating the importance of the specific GAG/carbohydrate backbone. The sulfate content of heparin/heparan sulfate was also important for the enhancement of amylin fibril formation in the order of heparin > N-desulfated N-acetylated heparin > completely desulfated N-sulfated heparin > completely desulfated N-acetylated heparin. These studies suggest that the enhancement effects of perlecan on amylin fibril formation are mediated primarily by both specific GAG chain backbone and GAG sulfate content, and implicate perlecan as an important macromolecule that is likely involved in the pathogenesis of islet amyloidosis.
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