Synthesis and Biological Evaluation of a Selective N- and P/Q-Type Calcium Channel Agonist

Abstract

The acute effect of the potent cyclin-dependent kinase (cdk) inhibitor (R)-roscovitine on Ca 2+ channels inspired the development of structural analogues as a potential treatment for motor nerve terminal dysfunction. On the basis of a versatile chlorinated purine scaffold, we have synthesized ca. 20 derivatives and characterized their N-type Ca 2+ channel agonist action. Agents that showed strong agonist effects were also characterized in a kinase panel for their off-target effects. Among several novel compounds with diminished cdk activity, we identified a new lead structure with a 4-fold improved N-type Ca 2+ channel agonist effect and a 22-fold decreased cdk2 activity as compared to (R)-roscovitine. This compound was selective for agonist activity on N-and P/Q-type over L-type calcium channels.

Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

“…Tsai, personal communication), cranial trauma [43], pain signaling (see 3.4. ), various viral infections [44], polycystic kidney disease [45, 46], glomerulonephritis [47–50], glaucoma [51, 52], Lambert-Eaton syndrome [53–55], deafness [56], Timothy syndrome [57–59], fibrosis [60], Cushing disease [61, 62] and diabetes [63]. These studies have made it to preclinical trials, with the exception of glaucoma, glomerulonephritis and Cushing disease where roscovitine entered clinical trials.…”

Synaptic Pathophysiology and Treatment of Lambert-Eaton Myasthenic Syndrome

“…An agonist that would increase Ca 2+ influx only through Ca 2+ channels that are already open in response to an action potential depolarization would be optimal. Recently, such a Ca 2+ channel agonist was developed and evaluated for effects on neurotransmitter release in LEMS model mouse NMJs [15,67]. This Ca 2+ channel agonist, termed GV-58 (Fig.…”

“…Liang et al (2012) strategically synthesized novel analogs of ( R )-roscovitine with the goal of creating a compound with specificity as a Ca 2+ channel agonist. GV-58 was generated as part of this lead optimization and was shown to have a significantly reduced potency as a Cdk antagonist and an increased efficacy and potency as an agonist of P/Q-type (Ca v 2.1) and N-type (Ca v 2.2) Ca 2+ channels [15,67]. When evaluated in a LEMS passive transfer model mouse NMJ, GV-58 significantly increased neurotransmitter release and also partially restored short-term plasticity characteristics [15].…”

New calcium channel agonists as potential therapeutics in Lambert–Eaton myasthenic syndrome and other neuromuscular diseases

“…Recently, Liang et al 21 reported the synthesis and assay of more than 20 analogs of R ‐roscovitine. The most promising analog that emerged from these studies (GV‐58; compound “13x” in Liang et al 21 ) was reported to have greater than 20‐fold lower cdk activity and three‐ to fourfold higher affinity for calcium channels 20,21 . Additionally, it is approximately fourfold more potent as a calcium channel agonist than R ‐roscovitine.…”

“…In an attempt to develop alternative therapeutic options, a novel strategy would be to target directly the calcium channels that regulate transmitter release. Recently, calcium channel gating modifiers with promise for treatment of neuromuscular disorders have been developed based on the parent molecule R ‐roscovitine 20,21 …”