Syntheses and Pharmacological Evaluations of Novel N‐Substituted Bicyclo‐Heptane‐2‐amines at <i>N</i>‐Methyl‐<scp>d</scp>‐Aspartate Receptors

Ateş‐Alagöz, Zeynep; Sun, Shengguo; Wallach, Jason; Adejare, Adeboye

doi:10.1111/j.1747-0285.2011.01124.x

Cited by 8 publications

(7 citation statements)

References 36 publications

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“…Target compounds 5a – f were synthesized as described in our previous publication [ 17 ]. Briefly, an appropriately substituted bromobenzene was reacted with magnesium to give a Grignard reagent which was reacted with commercially available norcamphor to give the desired alcohol.…”

Section: Resultsmentioning

confidence: 99%

“…Treatment with memantine or any of the test compounds resulted in a concentration dependent decline in numbers of viable cells at higher than 100 µM concentration. Our previous studies have indicated that compound 5a exhibits the highest affinity for NMDA receptor and greatest degree of protection from MES (maximal electroshock)-induced neural damage in rodents [ 17 ]. It is known, that under therapeutic conditions in patients, the serum level of memantine is about 1 µM [ 20 ].…”

Section: Resultsmentioning

confidence: 99%

“…We recently reported syntheses of several novel norcamphor (bicycloheptane)-based compounds which were designed as NMDA receptor un-competitive antagonists at the phencyclidine (PCP) biding site [17]. These studies generated six novel target compounds (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…Our group is involved in the design and syntheses of NMDA receptor antagonists as probes and possible therapies for neurodegenerative diseases with emphasis on AD [ 13 , 14 , 15 , 16 ]. We recently reported syntheses of several novel norcamphor (bicycloheptane)-based compounds which were designed as NMDA receptor un-competitive antagonists at the phencyclidine (PCP) biding site [ 17 ]. These studies generated six novel target compounds ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

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Toxicity Studies on Novel N-Substituted Bicyclo-Heptan-2-Amines at NMDA Receptors

et al. 2013

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Several novel norcamphor derivatives were designed and synthesized as uncompetitive NMDA receptor antagonists at the phencyclidine (PCP) binding site. Such compounds have potential as ligands for understanding and possibly the treatment of several neurodegenerative disorders and other glutamate-dependent disorders. We examined the toxic effects of the compounds as compared with memantine, an NMDA receptor antagonist that is FDA approved for treatment of Alzheimer’s disease, by testing these compounds on two cell lines: MDCK (to mimic blood brain barrier) and N2a (a neuronal cell line). The compounds showed toxicity profiles similar to those of memantine i.e., dose dependence above 100 μM and IC50 values above 150 μM for each cell line. It is known that the serum level of memantine under therapeutic conditions in patients is about 1 µM, indicting these compounds could have acceptable therapeutic indexes. 2-Phenyl-N-(2-(piperidin-1-yl) ethyl)bicyclo[2.2.1]heptan-2-amine (5a) was found to possess acceptable toxicity profiles in both cell lines. Interestingly, this was the compound identified as a good lead in our previous studies based on binding and anticonvulsant (MES) activity studies. It has thus emerged as an excellent lead compound for further studies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Toxicity Studies on Novel N-Substituted Bicyclo-Heptan-2-Amines at NMDA Receptors

et al. 2013

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“…The observations described in this and similar works are leading to new interests by us and others in the possibilities of discovery of NMDAR antagonists with reduced toxicities as potential compounds for treatment of depression and other CNS disorders [ 58 ].…”

Section: Nmda Receptor Antagonistsmentioning

confidence: 99%

NMDA Receptor Antagonists for Treatment of Depression

Ateş‐Alagöz

Adejare

2013

Pharmaceuticals

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Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA) receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker), and CGP 37849 (an NMDA receptor antagonist) have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery.

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Direct Access to Multifunctionalized Norcamphor Scaffolds by Asymmetric Organocatalytic Diels–Alder Reactions

et al. 2015

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A general organocatalytic cross‐dienamine activation strategy to produce chiral multifunctionalized norcamphor compounds having a large diversity in substitution pattern is presented. The strategy is based on a Diels–Alder reaction of an amino‐activated cyclopentenone reacting with most common classes of electron‐deficient olefins, such as nitro‐, ester‐, amide‐, and cyano‐substituted olefins, chalcones, conjugated malononitriles, CF3‐substituted enones, and fumarates. The corresponding norcamphor derivatives are formed in good yield, excellent enantioselectivities, and with complete diastereoselectivity. Furthermore, it is demonstrated that quaternary stereocenters and spiro norcamphor compounds can be formed with high stereoselectivity. The present development provides a simple, direct, and efficient approach for the preparation of important norcamphor scaffolds.

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Syntheses and Pharmacological Evaluations of Novel N‐Substituted Bicyclo‐Heptane‐2‐amines at N‐Methyl‐d‐Aspartate Receptors

Cited by 8 publications

References 36 publications

Toxicity Studies on Novel N-Substituted Bicyclo-Heptan-2-Amines at NMDA Receptors

Toxicity Studies on Novel N-Substituted Bicyclo-Heptan-2-Amines at NMDA Receptors

NMDA Receptor Antagonists for Treatment of Depression

Direct Access to Multifunctionalized Norcamphor Scaffolds by Asymmetric Organocatalytic Diels–Alder Reactions

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