Name:	RO5313534
Other Names:	MEM 3454, RG3487
Therapeutic Applications:	Mild to moderate Alzheimer disease
Therapy Types:	Oral, small molecule
Mechanisms:	RO5313534 is a selective nicotinic alpha-7 receptor partial agonist with 5HT3 receptor antagonist properties.
Development Status:	investigational in U.S.
FDA Phase:	Phase II/IIa/IIb
Primary Medical Role:	By activating nicotinic alpha-7 receptors as well as blocking 5HT3 receptors, RO5313534 increases the release of multiple neurotransmitters (e.g., acetylcholine and dopamine) that are involved in promoting cognitive function. RO5313534 has demonstrated improved learning and memory function in healthy and cognitively age-impaired animals.
Role in Alzheimer's Disease:	The nicotinic α7 receptor is highly expressed within the brain and has limited peripheral expression (e.g., macrophages, ganglionic neurons). Selective nicotinic α7 agonists like RO5313534 have been shown to increase cholinergic neurotransmission in a brain region-specific manner. Thus, it is hypothesized that α7 agonists may contribute to symptomatic treatment of Alzheimer disease through cholinergic mechanisms and have a better safety profile than observed with current therapies (Kem, 2000). In addition to neurodegeneration, the brains of Alzheimer disease patients display an abnormal accumulation of amyloid plaques and accumulations of abnormal tau filaments as neurofibrillary tangles. Amyloid plaques are insoluble aggregates of protein that are toxic to neurons. The major constituent of these plaques is the protein β amyloid. Preclinical data from several laboratories suggests that the amyloid protein from which these plaques are formed disrupts the function of the nicotinic α7 receptor. Furthermore, the most vulnerable neurons appear to be those that abundantly express the nicotinic α7 receptor, and internalization of amyloid-β1-42 (Aβ1-42) appears to be facilitated by the high-affinity binding of Aβ1-42 to the nicotinic α7 receptor on neuronal cell surfaces (D’Andrea and Nagele, 2005). Therefore, the nicotinic α7 receptor is a potentially important therapeutic target for disease modification treatment. Stimulation of nicotinic α7 receptors via agonist administration protects neurons from degeneration induced by Aβ1-42, further bolstering the idea that reduced nicotinic α7 receptor signaling is a mediator of age-related and Alzheimer’s-dependent cognitive decline (D’Andrea and Nagele 2005). Drugs that activate nicotinic α7 receptors would theoretically interfere with the neurotoxic effects of Aβ1-42 and prevent the pathophysiological and cognitive decline of Alzheimer’s patients. Additionally, since amyloid-β1-42 (Aβ1-42) binds to the nicotinic α7 receptor, agonists at this receptor site may potentially be important as disease-modifying treatments by competing with Aβ1-42 to bind to the receptor, thereby reducing the neurotoxic effects of Aβ1-42 and preventing further disease degeneration. Along this line, RO5313534 completely reversed the Aβ25-35-induced toxicity in primary cultured hippocampal neurons.
Pharmacological Role:	RO5313534 is an orally active nicotinic α7 receptor agonist. RO5313534 has high affinity (Ki = 6 nM) for nicotinic α7 receptor in rat brain membranes labeled with the radioligand [3H]methyllycaconitine, and RO5313534 inhibited binding of the 5HT3 receptor selective radioligand [3H]BRL43694 in human recombinant 5HT3 receptor expressed cells with a similar affinity (Ki = 2 nM). RO5313534 acted as a partial agonist (67 percent intrinsic activity) with an EC50 of 0.4 μM in the monkey wild-type nicotinic α7 receptor expressing cell line. RO5313534 also displayed an antagonist action against 5HT-induced contraction of guinea pig ileum. RO5313534 lacks affinity at α4β2 nicotinic receptors and has no activity at other nicotinic or other CNS receptor subtypes. Preclinically, RO5313534 has demonstrated oral efficacy in behavioral paradigms representing multiple cognitive domains (episodic, spatial, working, attentional, and executive memory functions) in young and aged rodents as well as aged non-human primates. Clinically, RO5313534 was generally well tolerated in Phase I studies of healthy young adults and healthy elderly adults, and no safety concerns have been encountered. RO5313534 produced a favorable pharmacokinetic profile with a plasma t½ of 8 hrs supporting once-daily dosing. Steady-state drug plasma levels were achieved by day 3 of administration and remained steady until termination of dosing. During the two weeks of dosing, no pharmacological tolerance was observed. Additionally, RO5313534 was assessed for cognitive enhancement in healthy adults using the Cognitive Drug Research (CDR) battery. Significant improvements in CDR performance were observed at the 15 mg dose following 13 days of administration. The primary cognitive measures showing significant improvement were on immediate and delayed word recall, accuracy, and recognition, as well as picture recognition and digit vigilance.
Companies:	Roche Pharmaceuticals
Notes:	A Phase II study of RO5313534 (MEM 3534 or RG3487) as an add-on treatment to Donepezil treatment in patients with mild to moderate Alzheimer Disease is currently recruiting participants. Phase II with Donepezil. A Phase I study of RO5313534 (MEM 3534 or RG3487) to evaluate safety and tolerability of memantine and RO5313534 treatment in healthy volunteers is not yet open for participant recruitment. Phase I with Memantine. This drug listing was updated September 23, 2010.

References

Nagele RG, D’Andrea MR, Anderson WJ and Wang HY. Intracellular Accumulation of beta-Amyloid1-42 in Neurons is Facilitated by the alpha7 Nicotinic Acetylcholine Receptor in Alzheimer’s Disease. Neuroscience. 110 (2): 199-211, 2002. Abstract

Grutzendler J and Morris JC. Cholinesterase Inhibitors for Alzheimer’s Disease. Drugs. 61 (1): 41-52, 2001. Abstract

Kem WR. The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer’s disease: study with DMXBA (GTS-21). Behavioural Brain Research. 113: 169-181, 2000. Abstract