PPAR Gamma Activators: Off-Target Against Glioma Cell Migration and Brain Invasion

Today, there is increasing evidence that PPARγ agonists, including thiazolidinediones (TDZs) and nonthiazolidinediones, block the motility and invasiveness of glioma cells and other highly migratory tumor entities. However, the mechanism(s) by which PPARγ activators mediate their antimigratory and anti-invasive properties remains elusive. This letter gives a short review on the debate and adds to the current knowledge by applying a PPARγ inactive derivative of the TDZ troglitazone (Rezulin) which potently counteracts experimental glioma progression in a PPARγ independent manner

M2 subtype preferring dibenzodiazepinone-type muscarinic receptor ligands: effect of chemical homo-dimerization on orthosteric (and allosteric?) binding

A series of new dibenzodiazepinone-type muscarinic receptor ligands, including two homo-dimeric compounds, was prepared. Sixteen representative compounds were characterized in equilibrium binding studies with [3H]N-methylscopolamine ([3H]NMS) at the muscarinic receptor subtype M2, and seven selected compounds were additionally investigated at M1, M3, M4 and M5 with respect to receptor subtype selectivity. The side chain of the known M2 preferring muscarinic receptor antagonist DIBA was widely varied with respect to chain length and type of the basic group (amine, imidazole, guanidine and piperazine). Most of the structural changes were well tolerated with respect to muscarinic receptor binding, determined by displacement of [3H]NMS. Compounds investigated at all subtypes shared a similar selectivity profile, which can be summarized as M2 > M1 ≈ M4 > M3 ≈ M5 (46, 50, 57, 62-64) and M2 > M1 ≈ M4 > M3 > M5 (1, 58). The homo-dimeric dibenzodiazepinone derivatives UNSW-MK250 (63) and UNSW-MK262 (64) exhibited the highest M2 receptor affinities (pIC50 = 9.0 and 9.2, resp.). At the M2 receptor a steep curve slope of -2 was found for the dimeric ligand 63, which cannot be described according to the law of mass action, suggesting a more complex mechanism of binding. In addition to equilibrium binding studies, for selected ligands, we determined pEC50,diss, an estimate of affinity to the allosteric site of [3H]NMS occupied M2 receptors. Compounds 58 and 62-64 were capable of retarding [3H]NMS dissociation by a factor > 10 (Emax,diss > 92%), with highest potency (pEC50,diss = 5.56) residing in the dimeric compound 64. As the monomeric counterpart of 64 was 100 times less potent (62: pEC50,diss = 3.59), these data suggest that chemical dimerization of dibenzodiazepinone-type M receptor ligands can enhance allosteric binding

Consequences of soluble ICAM-1 N-glycan alterations on receptor binding and signaling kinetics in mouse astrocytes

Soluble intercellular adhesion molecule-1 (sICAM-1) is elevated in the cerebrospinal fluid of patients with severe brain trauma and mouse sICAM-1 induces the production of macrophage inflammatory protein-2 (MIP-2) in mouse astrocytes. The production of MIP-2 is greatly enhanced when sICAM-1 contains sialylated complex-type N-glycans (sICAM-1-CT) as produced by Chinese hamster ovary (CHO) cells. By contrast, sICAM-1 from the Lec1 mutant of CHO cells (sICAM-1-HM), containing only high mannose-type N-glycans, is relatively inactive. Here we show that the Nglycans of sICAM-1-CT are mostly 2,3-sialylated bi-, tri-, and tetraantennary complex-type structures with varying amounts of core fucosylation. Unexpectedly, sICAM-1-CT and sICAM-1-HM bound equivalently to mouse astrocytes. Enhanced MIP-2 induction by sICAM-1-CT was associated with a more rapid, higher level, and prolonged MIP-2 response as well as sICAM-1-CT accumulation at the plasma membranes of mouse astrocytes. These results show that glycosylation of sICAM-1 contributes to its signaling properties at the astrocyte cell surface, and suggest that altered glycosylation which might arise as a result of inflammation could regulate the bioactivity of sICAM-1