Second-order nonlinear optical devices can be constructed by arranging the organic chromophores as pendants into a supramolecular backbone. [1][2][3][4] Enhancement of such nonlinearity has been observed when chromophores are organized in a fixed noncentrosymmetric arrangement as side groups of helical polyisocyanide and polypeptide. 1 However, no enhancement on the first hyperpolarizability β 0 values was observed for chromophores incorporated into a polymer with a flexible backbone. 4 The use of more rigid polymers such as polynorbornenes (PNB) derived from the ring-opening metathesis polymerization (ROMP) of norbornene derivatives in optoelectronic applications has been briefly explored. [5][6][7] The versatility of this methodology was demonstrated by synthesizing liquid crystalline polymers, 5 electroluminescent polymers, 6 and multiblock copolymers bearing various aryl chromophores to study their steady-state emission. 7 We wish to report the first examples of using dipolar conjugated moieties as pendants on a PNB backbone for the second-order nonlinear optical investigations.Four different monomers 1 were synthesized (Scheme 1, Supporting Information). 8 Grubb's ruthenium catalyst (RuCl 2 -(PCy 3 ) 2 (dCHPh) was employed to prepare the corresponding polymers 2. 8,9 The M n and polydispersity (PDI) of 2 as well as the absorption maxima in CHCl 3 solution of both 1 and 2 are summarized in Table 1. The profiles of the absorption spectra of 1 and 2 are similar, although the absorption maxima for 2 are somewhat blue-shifted in comparison to those of the corresponding 1. 10 Only 1d and 2d exhibited fluorescence emission at 497 and 492 nm, respectively, no excimer formation being detected. Thermogravimetrical analyses showed that polymers 2a and 2d were stable at 220 °C, whereas 2b and 2c remained intact below 180 °C.The hyper-Rayleigh scattering (HRS) method was employed to measure the β 0 values for 1 and 2 in CHCl 3 which are also tabulated in Table 1. 11,12 It is interesting to note that the β 0 values are significantly enhanced in 2 in comparison with those of the corresponding monomers 1. A plot of the β 0 (2)/β 0 (1) having the same pendant chromophore versus the average number of repetitive monomeric units, n, in 2 gave a linear relationship with

Background and purpose: Muraglitazar, a dual PPARa/g agonist, caused a robust increase in body weight in db/db mice. The purpose of the study was to see if this increase in weight was due to oedema and/or adipogenesis. Experimental approach: The affinity of muraglitazar at PPARa/g receptors was characterized using transactivation assays. Preadipocyte differentiation, expression of genes for adipogenesis (aP2), fatty acid oxidation (ACO) and sodium reabsorption (ENaCg and Na þ , K þ -ATPase); haemodilution parameters and serum electrolytes were measured to delineate the role of muraglitazar in causing weight gain vis a vis rosiglitazone. Key Results: Treatment with muraglitazar (10 mg kg À1 ) for 14 days significantly reduced plasma glucose and triglycerides. Reduction in plasma glucose was significantly greater than after similar treatment with rosiglitazone (10 mg kg À1 ). A marked increase in weight was also observed with muraglitazar that was significantly greater than with rosiglitazone. Muraglitazar increased aP2 mRNA and caused adipocyte differentiation in 3T3-L1 cells similar to rosiglitazone. It also caused a marked increase in ACO mRNA in the liver of the treated mice. Expression of mRNA for ENaCg and Na þ , K þ -ATPase in kidneys was upregulated after either treatment. Increased serum electrolytes and decreased RBC count, haemoglobin and haematocrit were observed with both muraglitazar and rosiglitazone. Conclusions and implications: Although muraglitazar has a better glucose lowering profile, it also has a greater potential for weight gain than rosiglitazone. In conclusion, muraglitazar causes both robust adipogenesis and oedema in a 14-day treatment of db/db mice as observed in humans.

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Objective:The aim of this study was to evaluate the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin with respect to mode of inhibition and its in vivo duration of inhibition and efficacy in type 2 diabetes animal model.Materials and Methods:DPP-IV enzyme assay was carried out in human plasma (10 μL) or human recombinant enzyme (10 ng) using H-Gly-Pro-AMC as a substrate. The competitive nature was estimated by plotting IC50 values measured at different substrate concentrations on the Y axis and substrate concentration on the X axis. The tight binding nature was estimated by plotting IC50 values measured at different plasma volumes on the Y axis and plasma volumes on the X axis. Fast binding kinetics was assessed by progressive curves at different inhibitor concentrations in the DPP-IV assay. The reversibility of the inhibitor was assessed by a dissociation study of the DPP-IV-sitagliptin complex. Durations of DPP-IV inhibition and efficacy were shown in ob/ob mice dosed at 10 mg/kg, p.o.Results:Sitagliptin is a competitive, reversible, fast and tight binding DPP-IV inhibitor. In ob/ob mice, 10 mg/kg, (p.o.) showed a long duration of inhibition of > 70% at 8 h. The duration was translated into long duration of efficacy (~ 35% glucose excursion at 8 h) in the same model and the effect was comparable to vildagliptin.Conclusion:The DPP-IV inhibitor sitagliptin behaves as a competitive, tight, and fast binding inhibitor. Sitagliptin differs mechanistically from vildagliptin and exhibits comparable efficacy to that of latter. The finding may give an understanding to develop-second generation DPP-IV inhibitors with desired kinetic profiles.

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