The Synthesis of Certain Derivatives and Analogues of (-)- and (+)-Galanthamine and an Assessment of their Capacities to Inhibit Acetylcholine Esterase.

Syntheses of certain di- and mono-oxygenated derivatives (e.g., 2 and 3, respectively) and analogues (e.g., 4, a D-ring monoseco-analogue of 2) of both the (-)- and (+)-enantiomeric forms of the alkaloid galanthamine [(-)-1] are reported. All have been assessed for their capacities to inhibit acetylcholine esterase but, in contrast to the predictions from docking studies, none bind strongly to this enzyme.

Assessment of anti-amyloidogenic activity of marine red alga G. acerosa against Alzheimer's beta-amyloid peptide 25-35.

OBJECTIVE: The amyloid hypothesis stimulates the discovery of compounds, which promotes beta-amyloid peptide (Aß) clearance, thereby altering the underlying pathophysiology of Alzheimer's disease (AD). Hence, the present study aims at the evaluation of anti-amyloidogenic potential of Gelidiella acerosa. METHODS: Prevention of Aß 25-35 aggregate formation and disaggregation of pre-formed fibrils by G. acerosa was evaluated in three phases by thioflavin T spectrophotometric assay. The results were further validated by confocal microscopic analysis. The conformational changes in the aggregated and non-aggregated Aß in the presence of G. acerosa were analyzed by Fourier transform infrared (FTIR) spectroscopic analysis. RESULTS: Phase-I study shows that G. acerosa reverts (4.56 ± 0.35 AU at 96 hours) the increase in fluorescence intensity of aggregated Aß (18.76 ± 0.99 AU) significantly (P < 0.05) as that of non-aggregated peptides, which suggests that G. acerosa prevents the formation of oligomers from monomers. The seaweed also prevents the fibril formation even after the aggregation process was initiated at 20 hours, which was verified by the significant (P < 0.05) decrease in the fluorescence intensity (2.94 ± 0.0721 AU) at 36 hours (Phase II). In addition, G. acerosa promotes fibrillar destabilization (Phase III), which was further substantiated by confocal microscopic analysis. Fourier transform infrared spectroscopy reveals that alteration in amide I and amide II band spectrum, which occurs due to Aß 25-35 aggregation was restored upon co-treatment with G. acerosa benzene extract. CONCLUSION: Overall, the results suggest that G. acerosa might have direct interaction with the aggregated peptide, thereby preventing oligomerization and fibrillation of Aß 25-35.

Current status and new developments with galantamine in the treatment of Alzheimer's disease.

Galantamine is a newly available cholinergic drug that offsets reductions in central cholinergic neurotransmission in Alzheimer's disease (AD) by specifically and reversibly inhibiting acetylcholinesterase (AChE) and by allosterically modulating nicotinic cholinergic receptors. The clinical impact of this latter mechanism of action has not been fully elucidated. Galantamine has favourable pharmacokinetic features including linear elimination kinetics, a relatively short half-life and high oral bioavailability. The efficacy of galantamine has been studied in an extensive clinical development program. During randomised, double-blind, placebo-controlled trials of up to 6 months' duration, galantamine 16 and 24 mg/day consistently produced a broad spectrum of beneficial effects on cognitive and non-cognitive AD symptoms. Patients' cognition, global function and abilities to perform both instrumental and basic activities of daily living were maintained, the emergence of behavioural symptoms was postponed and apparent reductions in caregiver burden were seen. In long-term studies (> or = 12 months), galantamine maintained cognitive and functional abilities at or near baseline levels for at least 12 months. Again, these benefits were associated with decreases in caregiver burden. The incidence of adverse events, which are typically mild or moderate in severity, is generally low with galantamine. Cholinergically mediated adverse events affecting mainly the gastrointestinal system can be minimised using the recommended slow dose-escalation regimen. Galantamine may therefore help reduce the overall burden and cost involved in caring for AD patients. Being approved for the treatment of mild-to-moderately severe AD in both the US and in Europe, with trials of its efficacy in other dementia types already yielding positive results, galantamine ranks as a first-line therapy for dementia.