1The novel cation channel blocker, LOE 908, was tested for its effects on Ca2+ entry and membrane currents activated by depletion of intracellular Ca2+ stores in human endothelial cells.2 LOE 908 inhibited store-operated Ca2+ entry induced by direct depletion of Ca2+ stores with 100 nM thapsigargin or 100 nM ionomycin with an EC50 of 2 giM and 4 giM, respectively. 3 LOE 908 did not affect thapsigargin-or ionomycin-induced Ca2+ release from intracellular stores up to concentrations of 3 gIM. 4 LOE 908 reversibly suppressed thapsigargin-as well as ionomycin-induced whole-cell membrane currents.5 The LOE 908-sensitive membrane conductance corresponded to a cation permeability of 5.5 and 6.9 fold selectivity for Ca2+ over K+ in the presence of thapsigargin and ionomycin, respectively. 6 Our results suggest that the isoquinoline, LOE 908 is a novel, potent inhibitor of the store-operated (capacitive) Ca2+ entry pathway in endothelial cells.

We recently reported the development of a receptor-modeling concept based on 5D-QSAR (quantitative structure-activity relationships) and which explicitly allows for the simulation of induced fit. In this account, we report its utilization toward the design of novel compounds able to inhibit the chemokine receptor-3 (CCR3). The study was based on a total of 141 compounds, representing four different substance classes. Using the Quasar software, we built two receptor surrogates that yielded a cross-validated r(2) value of 0.950/0.861 and a predictive r(2) of 0.879/0.798, respectively. The model was then employed to predict the activity of 58 hypothetical compounds featuring two variation patterns: lipophilic substitutions and amphiphilic H-bond acceptors. Eleven of the proposed ligands show a calculated binding affinity lower than any compound within the training set; the most potent candidate molecule is expected to bind at an IC(50) of 0.3 nM.

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