1 Aminoadamantane Derivatives

Tilley, Jefferson; Krämer, Manfred

doi:10.1016/s0079-6468(08)70315-1

Cited by 25 publications

(8 citation statements)

References 152 publications

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“…This anecdotal observation led to the demonstration that amantadine produces moderate symptomatic benefit in Parkinson's disease (particularly on tremor) and initiated interest in the aminoadamantanes for the treatment of neurological disease. Other anecdotal reports suggest that amantadine may have some activity in a variety of additional neurological conditions including tardive dyskinesia, chorea, and dementia (143).…”

Section: Introductionmentioning

confidence: 99%

“…Memantine was first synthesized in the early 1960s in a program at Eli Lilly & Co. to identify putative hypoglycemic agents, but was found to be devoid of such activity. In early animal studies, memantine demonstrated greater potency than amantadine in pharmacological models of Parkinson's disease, and although memantine probably has similar clinical activity, it has not been extensively evaluated for this condition (45,63,132,143). Anecdotal reports suggest that, while memantine is effective in treating Parkinson's disease symptoms, it might not be as active as amantadine for this indication (33).…”

Section: Introductionmentioning

confidence: 99%

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The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer's Disease

2003

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Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase in-hibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand-gated ion channels. However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations. Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist. Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory. However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD. In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons. Blockade of NMDA receptors by memantine could theoretically confer disease-modifying activity in AD by inhibiting the "weak" NMDA receptor-dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia. Moreover, recent in vitro studies suggest that memantine abrogates â-amyloid (Aâ) toxicity and possibly inhibits Aâ production. Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists , particularly those that act by a similar channel blocking mechanism such as dis-sociative anesthetic-like agents (phencyclidine, ketamine, MK-801). A variety of chan-275 nel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels). These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate-an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity-while sparing synaptic responses required for normal be-havioral functioning, cognition and memory.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer's Disease

2003

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“…However, MK-801 is only used as a research tool but not as a therapeutic agent. Hence, we used amantadine and memantine, NMDA antagonist effective in Parkinson's disease (Tilley and Kramer, 1981;Kornhuber etal., 1991;Chen et al, 1992;Rabey etal., 1992)to study potential synergism of action with the DA agonist bromocriptine and L-DOPA. Additionally, L-deprenyl a MAO-B inhibitor useful in the therapy of Parkinson's disease (Birkmayer etal., 1975) was used for comparison, as an agent having neuroprotective activity, not related to NMDA receptors blockade (Cohen and Spina, 1989;Knoll, 1992;Shoulson, 1992).…”

Section: Introductionmentioning

confidence: 99%

Memantine, amantadine, and L-deprenyl potentiate the action of L-DOPA in monoamine-depleted rats

Skuza¹,

Rogóż²,

Quack

et al. 1994

J. Neural Transmission

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Some treatments used for Parkinson's disease attenuate locomotor depression in rats treated with reserpine and alpha-methyl-p-tyrosine. In the present study memantine (2.5, 5.0 mg/kg), amantadine (10, 20 mg/kg) (both uncompetitive NMDA antagonists), and L-deprenyl (1.0, 5.0 mg/kg; MAO-B inhibitor) were tested for possible synergistic interactions with the dopamine agonists: bromocriptine (2.5, 5.0 mg/kg) and L-dopa (50, 100 mg/kg, +benserazide, 100 mg/kg). At higher doses, memantine (10 mg/kg), amantadine (40 mg/kg), bromocriptine (5 and 10 mg/kg) and L-dopa (100, 200 mg/kg) but not L-deprenyl (up to 10 mg/kg) produced a pronounced increase in locomotor activity when given alone. The combination of memantine, amantadine and L-deprenyl with bromocriptine did not result in synergism of action and, at best, an additive effect was seen. On the other hand the combination of these agents with L-dopa produced a pronounced synergistic effect. Hence, the clinical observation that coadministration of L-dopa with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinson's disease. Such a combination therapy should allow the use of lower doses of both drugs which may reduce the occurrence of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine, amantadine, and L-deprenyl.

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“…66 Although amantadine was first used clinically to treat the influenza virus, serendipitous observation by a clinician led to the observation that Parkinson's disease patients who were treated with amantadine for the flu had improved symptomatology. 67 Another important polycyclic cage amine, is memantine, an amino-adamantane used to clinically treat Alzheimer's disease. 68 -71 This polycyclic cage amine is an NMDA receptor antagonist.…”

Section: Adamantane Aminesmentioning

confidence: 99%

Polycyclic Compounds: Ideal Drug Scaffolds for the Design of Multiple Mechanism Drugs?

Schyf

Geldenhuys

2009

Neurotherapeutics

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Summary:Recently there has been a resurging interest in developing multi-functional drugs to treat diseases with complex pathological mechanisms. Such drug molecules simultaneously target multiple etiologies that have been found to be important modulators in specific diseases. This approach has significant promise and may be more effective than using one compound specific for one drug target or, by a polypharmaceutical approach, using a cocktail of two or more drugs. Polycyclic ring structures are useful as starting scaffolds in medicinal chemistry programs to develop multi-functional drugs, and may also be useful moieties added to existing structures to improve the pharmacokinetic properties of drugs currently used in the clinic or under development. This review attempts to provide a synopsis of current published research to exemplify the use of polycyclic compounds as starting molecules to develop multi-functional drugs.

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1 Aminoadamantane Derivatives

Cited by 25 publications

References 152 publications

The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer's Disease

The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer's Disease

Memantine, amantadine, and L-deprenyl potentiate the action of L-DOPA in monoamine-depleted rats

Polycyclic Compounds: Ideal Drug Scaffolds for the Design of Multiple Mechanism Drugs?

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