calcd. the action of the (EAATs) and plays an important role in the termination of the neuronal signaling process and in keeping the concentration of Glu below neurotoxic levels. In order to understand the physiological role of the different Glu receptor subunits, the development of subtype selective ligands is a key strategy. Such pharmacological tools, agonists, antagonists, and positive/negative modulators may be used for the functional studies of isolated receptors, neuronal tissue, and study, it is also evident that 1 provides several options for the introduction of substituents into unexplored areas of the receptor which may be advantageous in subsequent work to improve potency and/or the subtype selectivity SB366791 profile. Open in a separate window Figure 3 Superimposition of the low-energy conformation of 1 1 (type code) with the binding conformations of ATPO (black), UBP310 (green), and “type”:”entrez-nucleotide”,”attrs”:”text”:”LY466195″,”term_id”:”1258058612″,”term_text”:”LY466195″LY466195 (purple) obtained from X-ray crystal structures with PDB codes 1VSO, 2QS4, and 2F34, respectively. A retro synthetic analysis of 1 1 suggests (stereo selectivity and that high yields may be obtained by the use of a method previously developed in our laboratories. Open in a separate window Scheme 1 Synthetic Pathway toward 1Reagents and conditions: (a) TBSCl, Et3N, CH2Cl2; (b) BOC2O, Et3N, DMAP, CH2Cl2 (87% two steps); (c) LHMDS, THF, ?78 C, then PhSeCl; (d) H2O2, EtOAc, 0 C to RT (65% two steps); (e) 5, IC50oocytes and measured by TEVC electrophysiology. Shown are the pooled data normalized to the control response in the absence of antagonist from 5 to 6 experiments conducted in duplicate. GluK1, Glu = 100 M, IC50 = 18.6 M; GluK3, Glu = 5 mM, IC50 = 323 M. Inset: traces from one oocyte expressing the GluK3 mutant. Stimulations in duplicate at increasing concentrations SB366791 of 1 1 (in M): 0, 5, p85 10, 20, 50, 100, 200, 300, 1000; (= 10 and 4 Hz), 3.69 (dd, 1H, = 10 and 2 Hz), 2.72 (dt, = 17 and 10 Hz), 2.38 (qd, = 17, 9, and 2 Hz), 2.08 (m, 2H), 1.55 (s, 9H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). (5= 6 and 2 Hz), 6.07 (dd, 1H, = 6 and 2 Hz), 4.56 (m, 1H), 4.11 (dd, 1H, = 10 and 4 Hz), 3.67 (q, 1H, = 10 and 7 Hz), 1.52 (s, 9H), 0.83 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H). 3-Bromo-[(= 0.24) gave 7 as a white solid (1,24 g, 90%): mp = 68?69 C; []24589 = ?42.85 (= 0.49, CH2Cl2); 1H NMR 7.26 (m, 2H), 7.11 (br s, 1H), 7.05 (br d, 1H, = 7 Hz), 4.71 (s, 2H), 4.06 (p, 1H, = 4 and 2 Hz), 3.99 (dd, 1H, = 10 and 4 Hz), 3.78 (dd, 1H, = 10 and 2 Hz), 3.44 (dt, 1H, = 10, 3, and 2 Hz), 3.13 (q, 1H, = 18 and 10 Hz), 2.53 (dd, 1H, = 18 and 3 Hz), 1.52 (s, 9H), 0.94 (s, 9H), 0.91 (s, 9H), 0.10 (s, 6H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR 174.28, 150.00, 144.34, 142.44, 129.14, 125.02, 124.24, 83.16, 66.90, 64.99, 63.82, 40.16, 38.90, 28.25, 26.13, 26.03, ?5.05. (2= 0.23) gave 7 as a colorless oil (345 mg, 71%). []24589 = +2.34 (= 0.76, CH2Cl2); 1H NMR 7.22 (m, 1H), 7.13 (br d, 2H, = 7 Hz), 7.03 (br t, 1H, = 7 Hz), 4.67 (s, 2H), 4.00 ? 3.45 (m, SB366791 5H), 3.29 (m, 1H), 2.19 (m, 1 Hz), 1.86 (m, 1H), 1.44 (s, 9H), 1.44 (s, 9H), 0.90 (s, 9H), 0.85 (s, SB366791 9H), 0.06 (s, 6H), 0.00 (s, 6H); 13C NMR 154.41, 144.01, 143.54, 141.83, 128.63, 126.04, 125.13, 124.41, 79.55, 79.18, 65.74, 65.60, 65.15, 47.22, 46.64, 32.89, 32.05, 28.75, 26.15, ?5.04, ?5.20. (2= 0.23) gave 8 as SB366791 a colorless oil (417 mg, 94%). []24589 = ?11.52 (= 0.59, CH2Cl2); 1H NMR (= 7 Hz), 7.14 (br d, 2H, = 7 Hz), 7.04 (br d, 1H, = 7 Hz), 5.16 (t, 1H, = 5 Hz), 4.86 (br t,.

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