New non-L-subtypes Calcium channels blockers for applications on Nervous System Pathologies
Desarrollado por: IIS del Hospital Universitario de La Princesa
The alteration of cytosolic Ca2+ levels in neurons triggers excitotoxicityinduced cell death mechanisms and the subsequent neurodegeneration. The control of such intracellular Ca2+ by drugs blocking voltage-gated Ca2+ channels (VGCC) is one of the most common therapeutic strategies to treat cardiovascular diseases like hypertension, angina or arrhythmia. Thus, the so-called Ca2+-antagonists act in the circulatory system by reducing the Ca2+ influx through these channels, which are exclusively the L-type VGCC (CaV1.2). But this pharmacological activity has hindered their use in other therapies, like those from the central nervous system (CNS), though the blockade of VGCC has been promising target in in vitro models of neurodegenerative diseases, like Alzheimer’s or Parkinson’s, as well as stroke, whereby the neuronal death occurs initially via massive Ca2+ entry stimulated by high exposure to the excitatory neurotransmitter glutamate. One alternative to avoid cardiovascular side effects would be the design of VGCC blockers unable to interact with peripheral L-type channels. Indeed, the pharmacological blockade of P/Q or N-type VGCC has been of interest in nerve system pathologies such as epilepsia or pain; gabapentin, pregabalin, or ziconotide are marketed drugs acting on these last subtype of channels. Unfortunately, there are very few examples of selective drugs lacking effect on L-type VGCC, and mainly based in peptidomimetis or peptides toxins (e.g. ziconotide).
For this reason, we have proposed the design and preparation of smallsized drugs that block non-L-type VGCC selectively, not only to develop new medicines, but also to clarify the role of P/Q and N-type Ca2+ channels in the physiological and pathological processes where they have been implicated. About twenty compounds related to the natural product gramine have been synthesized. These compounds showed a decent blockade of the increase of cytosolic Ca2+ stimulated by depolarization (70 mM K+) in SHSY5Y. We selected the four best of them to monitorize Ca2+ currents induced by depolarizing pulses in bovine chromaffin cells in a whole-cell configuration. We selected that one blocking such Ca2+ current a 40%, and observed that this blockade is preserved and additive to that featured by the L-type VGCC nifedipine. But in presence of a toxin described to block both N and P/Q-type VGCCs. i.e. w-conotoxin MVIIA at 2 μM, or lead compound was unable to show an additional blockade, confirm that its blocking activity is exclusively carried out through non-L-type Ca2+ channels. Moreover, these family of compounds showed an important neuroprotective profile against toxic models of neurodegeneration, related to Ca2+ overload and Taupathies, where the most highlighted compound was that with demonstrated non-L type VGCC blocking activity.
Due to the key role of both enzymes GSK3β and AChE, oxidative stress and neuroinflammation in the development of AD pathology, these compounds have been designed specifically to target several pathological pathways. These compounds were designed as potential treatments for Alzheimer’s disease.
Estado de protección
Cooperación que se desea
Out-licensing opportunities or sponsored research.
Antonio Rodriguez Hita – Technology Transfer Manager
Tel: +34 915202476
- En busca de codesarrolladores, Transferible
- Tecnología sanitaria:
- Medicamentos - Farma