FFA2 (GPR43) has been identified as a receptor for short-chain fatty acids (SCFAs) that include acetate and propionate. FFA2 is highly expressed in islets, a subset of immune cells, and adipocytes. Although the potential roles of FFA2 activation in these tissues have previously been described, the physiological functions are still unclear. The potency for SCFAs on FFA2 is low, in the high micromolar to millimolar concentrations. To identify better pharmacological tools to study receptor function, we used high-throughput screening (HTS) to discover a series of small molecule phenylacetamides as novel and more potent FFA2 agonists. This series is specific for FFA2 over FFA1 (GPR40) and FFA3 (GPR41), and it is able to activate both the G␣ q and G␣ i pathways in vitro on Chinese hamster ovary cells stably expressing FFA2. Treatment of adipocytes with these compounds also resulted in G␣ i -dependent inhibition of lipolysis similar to that of endogenous ligands (SCFAs). It is noteworthy that these compounds not only acted as FFA2 agonists but also exhibited positive cooperativity with acetate or propionate. The observed allosteric modulation was consistent in all the functional assays that we have explored, including cAMP, calcium mobilization, guanosine 5Ј-[␥-thio]triphosphate binding, and lipolysis. Molecular modeling analysis of FFA2 based on human ␤ 2 -adrenergic receptor structure revealed potential nonoverlapping binding sites for the endogenous and synthetic ligands, further providing insight into the binding pocket for the allosteric interactions. This is the first report describing the identification of novel allosteric modulators with agonist activity for FFA2, and these compounds may serve as tools for further unraveling the physiological functions of the receptor and its involvement in various diseases.

Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.

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The near-field resonances of gold bowtie antennae are numerically modeled. Besides the shortrange surface plasmon polariton (SR-SPP) mode along the main axis of the structure, a coupled SPP mode is also found in the gap region (G-SPP). The influence of adhesion layers is considered, which depends on the refractive index and the absorption of the adhesion material and whether it is continuous or etched. A high refractive index causes the peak of the SR-SPP to redshift. High absorption quenches the intensity of the SR-SPP. The magnitude of influence depends on the overlap of the adhesion layer with the SR-SPP and G-SPP modes. The near-field resonance of the SPP mode on the top surface is also considered. An etched metal adhesion layer changes the near-field localization in the gap and causes the enhancement peaks at different heights within the gap to red-shift from top to bottom. A simple optimization method for the nearfield localization by the combination of different top and bottom layers is demonstrated.