Drug development for senile cognitive decline

Hershenson, Fred M.; Moos, Walter H.

doi:10.1021/jm00157a001

Cited by 49 publications

(23 citation statements)

References 3 publications

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“…The so-called "cholinergic hypothesis" for AD is based on a wide body of clinical and neurochemical evidence10•11 which indicates that the marked deficits in cognitive function which accompany AD can be most consistently related to selective degeneration of cholinergic neurons projecting from the nucleus basalis of Meynert into cortical regions. Two clear-cut strategies to accentuate cholinergic transmission have been evaluated extensively in the clinic: 12) 13 (1) inhibition of acetylcholinesterase (AChE) to potentiate the effects of endogenous acetylcholine and (2) therapeutic use of directly acting agonists at postsynaptic muscarinic receptors in the cortex.…”

mentioning

confidence: 99%

Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine Hydrochloride and Related Compounds

Sugimoto¹,

Iimura²,

Yamanishi³

et al. 1995

J. Med. Chem.

309

177

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Following the discovery of a new series of anti-acetylcholinesterase (anti-AChE) inhibitors such as 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine (1), we reported that its rigid analogue, 1-benzyl-4-(2-isoindolin-2-ylethyl)piperidine (5), had more potent activity. We have extended the structure-activity relationship (SAR) study for the rigid analogue and found that the 2-isoindoline moiety in compound 5 can be replaced with a indanone moiety (8) without a major loss in potency. Among the indanone derivatives, 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine (13e) (E2020) (IC50 = 5.7 nM) was found to be one of the most potent anti-AChE inhibitors. Compound 13e showed a selective affinity 1250 times greater for AChE than for butyrylcholinesterase. In vivo studies demonstrated that 13e has a longer duration of action than physostigmine at a dose of 5 mg/kg (po) and produced a marked and significant increase in acetylcholine content in rat cerebral cortex. We report the synthesis, SAR, and a proposed hypothetical binding site of 13e (E2020).

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mentioning

confidence: 99%

Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine Hydrochloride and Related Compounds

Sugimoto¹,

Iimura²,

Yamanishi³

et al. 1995

J. Med. Chem.

309

177

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“…Many compounds have been claimed to be endowed with cognition enhancing activity [34][35][36][37] (reviewed by Froestl and Maitre [38], for them the terms metabolic enhancer or cerebral stimulants have also been used) and few of them have reached the market for use in some countries for memory disturbances. Their use has been controversial and there is no general consensus on their efficacy in humans: the case of propentofylline (figure (1)), launched in 1994, may be illustrative.…”

Section: Cognition Enhancing Drugsmentioning

confidence: 99%

“…compounds that have been used or studied in more detail, starting from previous reviews [34][35][36][37][38], in particular that of Gouliaev and coworkers [57,58].…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Design and Study of Piracetam-like Nootropics, Controversial Members of the Problematic Class of Cognition-Enhancing Drugs

Gualtieri

Manetti²,

Romanelli³

et al. 2002

CPD

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Cognition enhancers are drugs able to facilitate attentional abilities and acquisition, storage and retrieval of information, and to attenuate the impairment of cognitive functions associated with head traumas, stroke, age and age-related pathologies. Development of cognition enhancers is still a difficult task because of complexity of the brain functions, poor predictivity of animal tests and lengthy and expensive clinical trials. After the early serendipitous discovery of first generation cognition enhancers, current research is based on a variety of working hypotheses, derived from the progress of knowledge in the neurobiopathology of cognitive processes. Among other classes of drugs, piracetam-like cognition enhancers (nootropics) have never reached general acceptance, in spite of their excellent tolerability and safety. In the present review, after a general discussion of the problems connected with the design and development of cognition enhancers, the class is examined in more detail. Reasons for the problems encountered by nootropics, compounds therapeutically available and those in development, their structure activity relationships and mechanisms of action are discussed. Recent developments which hopefully will lead to a revival of the class are reviewed.

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“…At present, an impressive array of chemical entities affecting synapse formation, neuronal differentiation, neurotransmission, nerve growth and repair, and several other functions are recognized. Acetylcholine has been a special target for investigations for almost two decades because its deficit, among other factors, has been held responsible for senile dementia and other degenerative cognitive disorders, including Alzheimer disease(113)(114)(115)(116). Receptors, which are activated by these chemicals, assume special importance in the present context.…”

mentioning

confidence: 99%

Ancient-Modern Concordance in Ayurvedic Plants: Some Examples

Dev¹

1999

Environmental Health Perspectives

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Drug development for senile cognitive decline

Cited by 49 publications

References 3 publications

Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine Hydrochloride and Related Compounds

Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine Hydrochloride and Related Compounds

Design and Study of Piracetam-like Nootropics, Controversial Members of the Problematic Class of Cognition-Enhancing Drugs

Ancient-Modern Concordance in Ayurvedic Plants: Some Examples

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