Memogain; supra-bioavailable nicotinic enhancer for the treatment of Alzheimer's disease

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Galantamine (Reminyl, Razadyne) is a potent allosterically potentiating ligand (APL) of nicotinic receptors and a moderate inhibitor of cholinesterases. In addition to its cognition-enhancing properties and mediated by its action on α7 nicotinic receptors, galantamine reduces amyloid toxicity and neuronal death. Manifestation of these properties in patients is limited by low dosing necessitated by need to control the usual gastrointestinal side effects (nausea, vomiting, diarrhoea) of cholinesterase inhibitors. We have developed a derivative of galantamine (“Memogain”) for the following purposes: increased bioavailability in the brain and reduced, if not negligible, GI side effects at efficacious doses. Animal model studies to test for enhanced bioavailability in the brain, reduced dosing schemes, absence of gastrointestinal side effects, potency in overcoming drug-induced cognitive impairment, tissue distribution of pro-drug and active moiety, pharmacokinetics and toxicity. Memogain is an inactive pro-drug of galantamine having more than 15fold higher bioavailability in the brain than the same doses of galantamine. Memogain is enzymatically cleaved in the brain to release its active moiety galantamine. In animal models of dementia, Memogain produced several fold larger cognitive improvement than galantamine, in the absence of any GI side effects. In the ferret dramatically reduced emetic responses were observed when Memogain was administered instead of galantamine. Should the advantageous properties of Memogain seen in animal models hold up to its action in man, we expect a dramatically improved side effects profile, no requirement for up-titration of dose to achieve satisfactory compliance, improved potency because of better delivery to the brain, and neuroprotective activity in addition to symptomatic cognitive enhancement. Memogain may become a second generation antidementive drug of combined symptomatic and disease-modifying properties.