Abstract
T-type calcium channel (CaV3.x) blockers are receiving increasing attention as potential therapeutics for the treatment of pathophysiological disorders and diseases, including absence epilepsy, Parkinson’s disease (PD), hypertension, cardiovascular diseases, cancers, and pain. However, few clinically approved CaV3.x blockers are available, and selective pharmacological tools are needed to further unravel the roles of individual CaV3.x subtypes. In this work, through an efficient synthetic route to the marine fungal product pseudellone C, we obtained bisindole alkaloid analogs of pseudellone C with a modified tryptophan moiety and identified two CaV3.2 (2, IC50 = 18.24 µM; 3, IC50 = 6.59 µM) and CaV3.3 (2, IC50 = 7.71 µM; 3, IC50 = 3.81 µM) selective blockers using a FLIPR cell-based assay measuring CaV3.x window currents. Further characterization by whole-cell patch-clamp revealed a preferential block of CaV3.1 activated current (2, IC50 = 5.60 µM; 3, IC50 = 9.91 µM), suggesting their state-dependent block is subtype specific.
Highlights
IntroductionMarine indole alkaloids have been widely explored for their therapeutic potentials, providing potential new drug leads for the treatment of a wide range of diseases including cancer, neurological disorders, and parasitic infections [2,3]
Alkaloids produced by marine animals are mostly potent cytotoxins evolved for defense [1].Marine indole alkaloids have been widely explored for their therapeutic potentials, providing potential new drug leads for the treatment of a wide range of diseases including cancer, neurological disorders, and parasitic infections [2,3]
We describe an efficient total synthesis of pseudellone C and several new bisindole alkaloid analogs. To investigate their pharmacological potential, we explored their activity in voltage-gated calcium channels (VGCCs) using FLIPR cell-based assays, and further characterized two potent low voltage-activated (LVA) T-type calcium channel (CaV 3.x) blockers by whole-cell patch-clamp using an automated electrophysiology platform, QPatch 16 X
Summary
Marine indole alkaloids have been widely explored for their therapeutic potentials, providing potential new drug leads for the treatment of a wide range of diseases including cancer, neurological disorders, and parasitic infections [2,3]. A family of tryptamine-based drugs used for the abortive treatment of migraine headaches, have been well established and characterized as selective agonists of 5-HT1 B and 5-HT1 D serotonin receptors [4]. Pharmacological studies on indole alkaloids mainly focus on the discovery of novel serotonin receptor agonists [5]. In a more recent study, a novel aryl indole compound was identified as a potent and selective blocker of N-type CaV 2.2, and showed robust in vivo efficacy in inflammatory and neuropathic rat pain models [7]
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