Oxostephanine, Thalmiculine, and Thaliphyline—Three Isoquinoleine Alkaloids That Inhibit L-Type Voltage-Gated Ca2+ Channels

Abstract

The isoquinoline alkaloids (IAs) represent a large and diverse subfamily of phytochemicals in terms of structures and pharmacological activities, including ion channel inhibition. Several IAs, such as liriodenine (an oxoaporphine) and curine (a bisbenzylisoquinoline (BBIQ), inhibit the L-type voltage-gated Ca2+ channels (LTCC). In this study, we aimed to search for new blockers of LTCC, which are therapeutic targets in neurological and cardiovascular diseases. We set up a screening assay using the rat pituitary GH3b6 cell line, which expresses two LTCC isoforms, Cav1.2 and Cav1.3. Both LTCC subtypes can be indirectly activated by KCl concentration elevation or directly by the dihydropyridine (DHP), BAY K8644, leading to an increase in the intracellular Ca2+ concentration ([Ca2+]i). These Ca2+ responses were completely blocked by the selective LTCC DHP inhibitor, nifedipine. Thereby, 16 selected IAs were tested for their ability to inhibit KCl and BAY K8644-induced Ca2+ responses. We then identified three new potent LTCC blockers, namely, oxostephanine, thaliphyline, and thalmiculine. They inhibited LTCC with IC50 values in the micromolar range through interaction to a binding site different to that of dihydropyridines. The two subfamilies of IAs, oxoaporphine with oxostephanine, and BBIQs with both thalyphilline and thalmiculine, constitute interesting pharmacophores for the development of future therapeutic leads for neurological and cardiovascular diseases.