PS75

Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α 2A -adrenergic receptor (α 2A AR), seeking new α 2A AR agonists chemotypes that lack the sedation conferred by known α 2A AR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G i and G o signaling. Experimental structures of α 2A AR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit ‘9087 [mean effective concentration (EC 50 ) of 52 nanomolar] and two analogs, ‘7075 and PS75 (EC 50 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.

Thermal annealing was used for the bottom-up fabrication of morphologically controlled gold-block-copolymer (Au-BC) nanocomposites. Three different blends formed by polystyrene (PS) homopolymer and PS-coated gold nanoparticles (PSSH@Au) were used as modifiers of asymmetric polystyrene-b-polymethylmethacrylate (PS-b-PMMA): PS26/PS26SH@Au, PS75/PS75SH@Au and PS167/PS167SH@Au (where the subscripts refer to the number of styrene monomeric units).The results indicated that all three blends used as modifiers (PSn/PSnSH@Au) were successfully located in the PS phase during thermally induced BC self-assembly for a composition range from 5 to 43 wt% without macro-phase separation. The PSnSH@Au moiety experienced molecular desorption, nanocrystal core coalescence and partial molecular re-encapsulation processes during thermal annealing, leading to sphere-like gold NPs with a larger average size (without exceeding an interdomain distance). Ligand chain length regulated the degree of coalescence and re-encapsulation, defining ultimate core size. Furthermore, proper combination of chain length and composition enabled tuning of NP partitioning and arrangement on different length scales through thermally activated cooperative assembly processes. These results have not only significant impact for establishing thermal processing as a useful tool for the precise control of NP size and distribution, but also much broader implications for many nanoparticle-based technologies.