Name:	MEM 1003
Therapeutic Applications:	In development for Alzheimer disease and bipolar disorder
Therapy Types:	Pharmaceutical: small molecule
Mechanisms:	MEM 1003 is a neuronal L-type calcium channel antagonist.
Development Status:	investigational in U.S.
FDA Phase:	Phase II/IIa/IIb
Primary Medical Role:	By blocking neuronal voltage-gated L-type calcium channels, MEM 1003 may regulate the flow of calcium within CNS neurons.
Role in Alzheimer's Disease:	One of the earliest manifestations of Alzheimer disease is an impaired regulation of calcium within CNS neurons. Neuronal calcium levels are regulated by specific proteins known as L-type calcium channels. Abnormal regulation of these channels is believed to be an early step in the Alzheimer disease process, first impairing the pathways required for memory and other cognitive functions and eventually causing the death of neurons. In support of this hypothesis, Yagami et al. (2004) have shown that a selective L-type calcium channel blocker (S-312-d) significantly prevented primary rat cortical neurons from Aβ-induced Ca2+ influx, suppressed apoptotic features such as DNA fragmentation, and reduced cell death. Acting independently of NMDA receptors, postsynaptic L- type voltage-gated calcium channel activity is required for LTP in the CA1 region of the hippocampus. Hippocampus- specific inactivation of L-type Ca channel gene Cav1.2 in mice resulted in severely impaired hippocampus-dependent spatial memory (Moosmang et al., 2005). Thus, calcium is believed to be an essential mediator of long-term memory formation. However, it has also been shown that 1 μM Aβ42 significantly impairs LTP in rat hippocampal CA1 pyramidal neurons without affecting voltage dependent calcium channel currents (Nomura et al., 2005). Nimodipine, the parent compound of MEM 1003, has shown some benefits in clinical trials with Alzheimer disease (Fritze and Walden, 1995) and has demonstrated efficacy in reduction in Aβ42 production in rat cortical neurons that is specifically induced by increases in cytosolic calcium concentration (Pierrot et al., 2004). However, meta-analysis of clinical studies that test nimodipine for efficacy in dementia demonstrated that nimodipine does not swiftly improve manifestations of the disease but rather seems to slow progression (Lopez-Arrieta and Birks, 2002). MEM 1003 has demonstrated enhanced learning effects as compared to vehicle in aged rabbits tested on eyeblink conditioning tests of learning, supporting the notion that MEM 1003 may reduce age-related cognitive impairment in a manner similar to its parent compound (Rose et al., 2006). Of note: the rabbit eyeblink study was conducted with subcutaneous administration of MEM 1003; aged rodent trace fear conditioning was IP and PO administration (Lowe et al., 2006). Further, modulation of the calcium flow may impact the progression of the disease by protecting these neurons from further damage caused by the amyloid plaques.
Pharmacological Role:	Nimodipine[(2-methoxyethyl)-1,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)-3,5- pyrinedicarboxylate, an anti- hypertensive agent, is an isopropyl calcium channel blocker; it has lipophilic properties and can easily cross the blood-brain barrier. Its primary action is to bind to L-type receptors and reduce the number of open channels conveying calcium ions through the cell membrane, thereby restricting influx of calcium ions into cells. It also has anti-vasoconstrictive and vasodilatatory action on arterioles (Lopez-Arrieta and Birks, 2002). MEM 1003 is an orally available dihydropyridine compound related to nimodipine, with superior pharmacokinetic properties (nimodipine has a very short half-life in humans) and reduced potency for cardiovascular effects, particularly blood pressure- lowering effects (Rose, 2006; Lowe et al, 2006).
Side Effects:	Unknown
Evidence pro its efficacy:	MEM 1003’s parent compound nimodipine has been used extensively to verify the link between calcium channel regulation and neurodegeneration. Nimodipine attenuates Aβ-induced neurotoxicity via blocking Ca2+ infux (Weiss et al., 1994) and reduces Aβ42 production in response to Ca2+. Similar beneficial effects have also been found with MEM 1003 (Lowe et al., 2006). MEM 1003’s parent compound nimodipine is currently frequently prescribed for cognitive impairment and dementia in several continental European countries (Lopez-Arrieta and Birks, 2002).
Evidence con its efficacy:	Nimodipine’s efficacy in clinical trials of dementia failed to merit US FDA approval because the efficacy was unconvincing. In addition, the pharmacokinetic properties and adverse effect profile of nimodipine limited dose escalation to achieve more consistent beneficial effects. MEM 1003 was developed to address those concerns. MEM 1003 has better stability and a longer terminal half-life than nimodipine in preclinical studies, and has no effect on blood pressure at highest dose tested (180mg bid) in Phase 1a and 1b clinical trials (Lowe et al., 2006). Nimodipine has been shown to preferentially vasodilate cerebral blood vessels before affecting peripheral blood vasculature (Kazda and Towart, 1982). MEM 1003 also showed cerebral selectivity (Lowe et al., 2006), suggesting it may improve cerebral blood flow without affecting blood pressure, as evident from Phase 1 clinical trials. The vasodilation effects of nimodipine are of concern in MEM 1003 and related compounds. This drug property may cause a drop in blood pressure, although it might also improve blood flow into the brain.
Companies:	Memory Pharmaceuticals Corporation
Notes:	Phase II testing is complete. Memory Pharmaceuticals was acquired by Roche (Novemeber 2008). Future development of MEM1003 is uncertain. This record last updated Dec 19, 2008.

References

Rose GM, Ong VS, Woodruff-Pak DS. Efficacy of MEM 1003, a novel calcium channel blocker, in delay and trace eyeblink conditioning in older rabbits. Neurobiol Aging. 2006 Apr 16; [Epub ahead of print] Abstract

Lowe D, De Vivo M, Tripodi C, Kornecook T, Kogan J, Tombaugh G, Wang D, Deng C, Dizon M, Murray M, Ong V and Rowe W. MEM 1003, A novel L-type CA2+ channel modulator, as a potential therapeutic for Alzheimer's disease. ICAD 2006, abstract P4-437, Madrid.

Nomura I, Kato N, Kita T, Takechi H. Mechanism of impairment of long-term potentiation by amyloid beta is independent of NMDA receptors or voltage-dependent calcium channels in hippocampal CA1 pyramidal neurons. Neurosci Lett. 2005 Dec 31;391(1-2):1-6. Abstract

Moosmang S, Haider N, Klugbauer N, Adelsberger H, Langwieser N, Muller J, Stiess M, Marais E, Schulla V, Lacinova L, Goebbels S, Nave KA, Storm DR, Hofmann F, Kleppisch T. Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor-independent synaptic plasticity and spatial memory. J Neurosci. 2005 Oct 26;25(43):9883-92. Abstract

Yagami T, Ueda K, Sakaeda T, Itoh N, Sakaguchi G, Okamura N, Hori Y, Fujimoto M. Protective effects of a selective L- type voltage-sensitive calcium channel blocker, S-312-d, on neuronal cell death. Biochem Pharmacol. 2004 Mar 15;67 (6):1153-65. Abstract

Lopez-Arrieta JM, Birks J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev 2002;(3):CD000147. Abstract

Fritze J, Walden J. Clinical findings with nimodipine in dementia: test of the calcium hypothesis. J Neural Transm Suppl. 1995;46:439-53. Abstract

Kazda S, Towart R. Nimodipine: a new calcium antagonistic drug with a preferential cerebrovascular action. Acta Neurochir (Wien). 1982;63(1-4):259-65. Abstract