2-aminoethyl diphenylborinate (2-APB) is a well known effector of the store-operated Ca(2+) entry of several cell types such as immune cells, platelets and smooth muscle cells. 2-APB has a dual effect: potentiation at 1-5μM and inhibition at>30μM. Unfortunately it is also able to modify the activity of other Ca(2+) transporters, and thus, can not be used as a therapeutic tool to control the leukocyte activity in diseases like inflammation. Previously, we have shown that SOCE potentiation by 2-APB depends on the presence of the central boron-oxygen core (BOC) and that the phenyl groups determine the sensitivity of the molecule to inhibit and/or potentiate the SOCE. We hypothesized that by modifying the two phenyl groups of 2-APB, we could identify more efficient and specific analogues. In fact addition of methoxyl groups to one phenyl group greatly decreased the potentiation ability without any significant effect on the inhibition. Surprisingly when the free rotation of the two phenyl groups was blocked by a new hydrocarbon bridge, the BOC was no longer able to potentiate. Furthermore, larger aryl groups than phenyl also impaired the activity of the BOC. Thus, the potentiation site in the Ca(2+) channel is not accessible by the BOC when the lateral groups are too large or unable to freely rotate. However, these molecules are potent inhibitors of store operated calcium entry with affinities below 1μM and they can block the activation of the Jurkat T cells. Thus it is possible to characterize 2-APB analogues with different properties that could be the first step in the discovery of new immunomodulators. This article is part of a Special Issue entitled: Calcium Signaling In Health and Disease.