P4–437: MEM 1003, a novel L–type Ca2+ channel modulator, as a potential therapeutic for Alzheimer's disease
David LoweMichael De VivoCrista TripodiTom J. KornecookJeff H. KoganGeoff TombaughDaguang WangChengjun DengMarc DizonMichael P. MurrayVoon OngWayne Rowe
0
Citation
0
Reference
10
Related Paper
Abstract:
Neurons must maintain appropriate ion gradients in order to function properly; as they age, or are affected by toxins such as beta amyloid peptides, neurons lose this ability. An increase in Ca2+ entry into the cell alters activity of Ca2+–dependent proteins such as ion channels and proteolytic enzymes which may adversely affect many cell functions. Excessive Ca2+ entry may be exacerbated by an increase in density of L–type Ca2+–channels reported to occur in aging and in Alzheimer's disease. Blocking voltage–regulated calcium channels may facilitate the ability of neurons to maintain appropriate calcium levels and function properly. Memory Pharmaceuticals is developing MEM1003, a dihydropyridine (DHP) Ca2+ channel modulator, for Alzheimer's disease. MEM1003 is equipotent to nimodipine, another DHP, in blocking L–type Ca2+currents in CA1 hippocampal neurons, but it is 4 to 15–fold less potent in relaxing rat thoracic smooth muscle when compared to other DHPs like nimodipine, nitrendipine or felodipine. This suggests that MEM1003 may have a superior safety profile. MEM1003 is a single enantiomer, unlike nimodipine and many other DHP drugs, and may lack potential off–target pharmacological activities present in racemic mixtures. We will present data showing the effectiveness of MEM1003 in improving cognitive performance in multiple preclinical behavior models at plasma exposure levels consistent with its affinity for the DHP binding site. One proposed mechanism for the procognitive effects of MEM1003 is that it mediates a reduction in the slow afterhypolarization (sAHP) of CA1 pyramidal neurons. An enlarged sAHP, functionally linked to L–type Ca2+channels, may interfere with cognitive behaviors. Our recent findings have demonstrated that sAHP amplitude co–varies with spatial learning ability in aged rats (Tombaugh et al., 2005). The pharmacokinetic and safety profiles of MEM1003 were recently studied in double–blind, randomized, placebo–controlled Phase 1A and Phase 1B clinical trials. MEM1003 was well tolerated up to the highest dose tested of 180 mg twice daily. The safety data and pharmacokinetics of MEM1003 in these studies will be presented and the relevance of the exposure levels to preclinical animal efficacy models and toxicology studies will be discussed. MEM1003 is currently in a Phase 2A clinical trial for Alzheimer's disease.Keywords:
Nimodipine
Nimodipine
Cite
Citations (26)
N-type calcium channel
L-type calcium channel
Calcium channel blocker
Channel blocker
Cite
Citations (33)
Female aged rats treated with nimodipine, a calcium-blocker dihydropyridine derivative, were submitted to a psychological-stress situation. Nimodipine at the doses of 3 and 6 mg/Kg antagonized the stress-related body-weight decrease and lethality. These findings seem to validate the role of Ca-mediated mechanisms in the physiopathology of stress and the protective effects of the Ca-blockers in the stress-related illnesses.
Nimodipine
Pathophysiology
Psychological stress
Cite
Citations (2)
Nitrendipine
P-type calcium channel
N-type calcium channel
Membrane channel
Cite
Citations (32)
iAbstract Background: Several studies have shown that the dihydropyridine calcium channel blockers such as nimodipine, nifedipine, and amlodipine have anticonvulsant effect in a range of animal models. Objective: The aim of this study was to investigate the effects of nimodipine, nifedipine and amlodipine on PTZ-induced seizure threshold with further comparison of results in mice. Methods: In 2007, this experimental study was carried out in School of Veterinary Medicine of Tabriz Islamic Azad University. Male NMRI mice were randomly divided into groups of ten members. Mice were intraperitoneally pretreated with vehicle or dihydropyridines (0.5-20 mg/kg) before the determination of intravenously PTZ-induced seizure threshold. Findings: The PTZ seizure threshold was 33.4±0.42 mg/kg in control group. In animals pretreated with nimodipine, nifedipine and amlodipine, the PTZ seizure threshold dose-dependently increased, compared with vehicle group. Nimodipine and nifedipine were found to have the highest and lowest anticonvulsant effects, respectively. Conclusion: Our results suggest that the dihydropyridine Ca 2+ channel blockers induce an anticonvulsant activity probably via an antagonistic effect on voltage-gated Ca 2+ channels.
Nimodipine
Amlodipine
Seizure threshold
Cite
Citations (3)
This study examined effects of the dihydropyridine calcium channel antagonist, nimodipine, on operant self-administration of ethanol, under a progressive-ratio schedule of reinforcement, by hooded Lister rats. Calcium channel antagonists have been reported to decrease the ethanol withdrawal syndrome, the development of tolerance to ethanol and ethanol consumption; and dihydropyridine binding site density in the central nervous system (CNS) is increased by chronic alcohol treatment. In addition, these drugs decrease reinforcing effects of psychostimulants. In the present studies, nimodipine was administered, once weekly, at either 10 or 50 mg/kg intraperitoneally (i.p.). At 10 mg/kg, nimodipine decreased the break point, and number of reinforcers obtained, for ethanol concentrations of 5, 10 and 15%. At 50 mg/kg, nimodipine only decreased the break point, and number of reinforcers, for 5% ethanol. Responding for higher concentrations of ethanol was unaffected by nimodipine, as was responding when ethanol was replaced by water. The break point for 10% sucrose, but not for 1% or 0.1%, was decreased by 50 mg/kg nimodipine, but 10 mg/kg nimodipine had no effect on sucrose-reinforced responding. The 50 mg/kg dose of nimodipine decreased motor activity, but 10 mg/kg nimodipine only slightly decreased static activity counts. The results suggest that nimodipine, at the lower dose tested, decreased the reinforcing properties of low concentrations of ethanol. © 1999 Lippincott Williams & Wilkins.
Nimodipine
Cite
Citations (13)
Nimodipine
Amlodipine
Cite
Citations (83)
At least four calcium channel subtypes (P, T, N, and L) have now been classified on the basis of their biophysical and/or pharmacological properties. L-type channels, a channel family particularly important to physiological function of the cardiovascular system, are identified by their slow voltage- and calcium-dependent inactivation as well as their sensitivity to dihydropyridine (DHP) calcium channel antagonists. In this study, we report the results of experiments in which we have measured the DHP modulation of recombinant calcium channel activity in cells transfected with alpha 1 subunits of cardiac and smooth muscle L-type calcium channels. We find subunit-dependent differences in the voltage and concentration dependence of channel modulation. Our results provide evidence for a molecular basis for DHP sensitivity of heart and smooth muscle calcium channels and, additionally, indicate that, even within one family of calcium channels, slight differences in channel structure can cause marked differences in channel pharmacology.
R-type calcium channel
N-type calcium channel
L-type calcium channel
Cardiac action potential
Cite
Citations (128)
The dihydropyridine-sensitive calcium channel of the rabbit skeletal muscle is the first voltage-gated calcium channel which has been purified and biochemically characterized. The alpha 1-subunit, a 165 kDa protein, of the purified dihydropyridine receptor contains all regulatory sites of a L-type calcium channel and the calcium conducting unit. The purpose of this review is to summarize and discuss recent findings on the structure and possible function of the skeletal muscle calcium channel subunits.
N-type calcium channel
R-type calcium channel
L-type calcium channel
Cite
Citations (12)
Voltage-sensitive calcium channels in different tissues have diverse functional properties. Polyclonal antibodies (PAC-2) against the α subunits of purified rabbit skeletal muscle calcium channels immunoprecipitated calcium channels labeled with the dihydropyridine PN200-110 from both skeletal muscle and brain. The immunoreactivity of PAC-2 with the skeletal muscle channel was greater than that with the brain calcium channel and was absorbed only partially by prior treatment with the brain channel. PAC-2 specifically recognized a large peptide in synaptic plasma membranes of rabbit brain with an apparent molecular size of 169,000 daltons. This protein resembles an α subunit of the skeletal muscle calcium channel in apparent molecular weight, antigenic properties, and electrophoretic behavior after reduction of disulfide bonds. Thus, the dihydropyridine-sensitive calcium channel of rabbit brain has an α subunit that is homologous, but not identical, to those of the skeletal muscle calcium channel. The different functional properties of these two calcium channels may result from minor variations in structurally similar components.
R-type calcium channel
N-type calcium channel
P-type calcium channel
Polyclonal antibodies
Cite
Citations (83)