Interactions of β-carbolines with the benzodiazepine receptor: Structure-activity relationships

Robertson, Harold A.; Baker, Glen B.; Coutts, Ronald T.; Benderly, A; Locock, R.A.; Martin, Ian L.

doi:10.1016/0014-2999(81)90515-x

Cited by 39 publications

(12 citation statements)

References 9 publications

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“…The structure-affinity analysis suggested that the presence of a 3-position substituent (e. g. amide, ester, carbinol) and a fully aromatic ring system are optimal for BZR binding; while the tetrahydro--carbolines demonstrated considerably less affinity for BZR than their fully aromatic counterparts [79][80][81]. In accordance with this rule, Glennon et al [82] found that the DH Cs lacked the affinity for BZR, even when a 3-position ester group was incorporated into the ring of harmalan (9), the compound did not bind to BZRs [82].…”

Section: Interaction With Receptorsmentioning

confidence: 99%

β-Carboline Alkaloids: Biochemical and Pharmacological Functions

Cao

Peng²,

Wang³

et al. 2007

CMC

622

353

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beta-Carboline alkaloids are a large group of natural and synthetic indole alkaloids with different degrees of aromaticity, some of which are widely distributed in nature, including various plants, foodstuffs, marine creatures, insects, mammalians as well as human tissues and body fluids. These compounds are of great interest due to their diverse biological activities. Particularly, these compounds have been shown to intercalate into DNA, to inhibit CDK, Topisomerase, and monoamine oxidase, and to interact with benzodiazepine receptors and 5-hydroxy serotonin receptors. Furthermore, these chemicals also demonstrated a broad spectrum of pharmacological properties including sedative, anxiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic as well as antimicrobial activities. In this review, we summerized the biochemical and pharmacological functions of beta-carboline alkaloids.

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Section: Interaction With Receptorsmentioning

confidence: 99%

β-Carboline Alkaloids: Biochemical and Pharmacological Functions

Cao

Peng²,

Wang³

et al. 2007

CMC

622

353

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“…131 However, the presence of a substituent at position 9 dramatically compromised the affinity for GABA A receptor (IC 50 > 0.29 μM for 9-methyl counterparts of 87b, 89d, and 89e; > 5.0 μM for other derivatives). 115,117,127,128 A few other chemical groups led to similar affinity upon further pharmacomodulation at position 3. Among them, the propyl ketone 87g, nitrile 87h, isothiocyanate 87i and propoxy 87j yielded the best results (IC 50 < 11 nM).…”

Section: ■ Phosphodiesterase Type 5 (Pde5) Inhibitorsmentioning

confidence: 98%

“…117−120 Reduced versions of β-CCM 87b and β-CCE 87c showed far weaker activities (IC 50 = 6.0 μM). 115 In addition, the early discovery of β-carboline-based agonists and antagonists prompted research groups to establish enlightening structure-efficacy relationships. One striking feature was the shift of the β-carboline 3-esters efficacy along an inverse agonist−agonist continuum, as the carbon chain of the ester became bulkier (Figure 17).…”

Section: ■ Phosphodiesterase Type 5 (Pde5) Inhibitorsmentioning

confidence: 99%

“…This is especially the case with norharmane 9a and harmane 9b (IC 50 = 1.6–8.2 μM and 7.2–25 μM, respectively, Figure ), while further substitutions and partial or complete saturation of the pyridine ring led to an activity drop (e.g., IC 50 > 100 μM for 1 – 3 , Figure ). − In contrast, the introduction of an ester group at position 3 produced compounds with far better affinities, in the nanomolar range. β-CCM 87b , β-CCE 87c together with higher homologues 87d and 87e thus shared similar IC 50 values of 1–10 nM, and seemingly constitute the optimal steric hindrance window, as both the carboxylic acid 87a and the CH 2 t -Bu 87f analogues were less active (IC 50 = 31–33 μM and 0.75 μM, respectively, Figure ).…”

Section: γ-Aminobutyric Acid Receptors (Gabaa) Ligandsmentioning

confidence: 99%

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β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

et al. 2021

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The natural β-carboline alkaloids display similarities with neurotransmitters that can be favorably exploited to design bioactive and bioavailable drugs for Alzheimer's disease (AD) therapy. Several AD targets are currently and intensively being investigated, divided in different hypotheses: mainly the cholinergic, the amyloid β (Aβ), and the Tau hypotheses. To date, only symptomatic treatments are available involving acetylcholinesterase and NMDA inhibitors. On the basis of plethoric single-target structure−activity relationship studies, the β-carboline scaffold was identified as a powerful tool for fostering activity and molecular interactions with a wide range of AD-related targets. This knowledge can undoubtedly be used to design multitarget-directed ligands, a highly relevant strategy preferred in the context of multifactorial pathology with intricate etiology such as AD. In this review, we first individually discuss the AD targets of the β-carbolines, and then we focus on the multitarget strategies dedicated to the deliberate design of new efficient scaffolds.

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“…3-Carboline compounds have been proposed as a candidate for the endogenous ligand of the benzodiazepine receptor (14,15), which is tightly associated with the GABA-CI ionophore complex (16). Robertson et al (14) have reported that harmine displaced specifically-bound…”

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confidence: 99%

Estimation of harmine and its derivatives by HPLC : Correlation of brain harmine levels with jumping behavior in rats.

Moroi

Kuga

1987

Jpn.J.Pharmacol

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Abstract-Brainharmine was simply and sensitively determined by high perfor mance liquid chromatography (HPLC), and the relationship between brain harmine concentrations and the jumping behavior induced by harmine and apomorphine was investigated. The concentration of harmine and the peak height in HPLC showed a good correlation, and the detection limit was 0.05 pmole harmine.In rats treated with 2, 5 and 10 mg/kg of harmine, the concentrations of harmine in the brain cortex were 9.0, 21.3 and 43.1 nmole/g tissue (wet wt.), respectively. The regional brain harmine concentrations and the jumping activity measuring by a scoring system increased with increasing doses of harmine administered, and there was a direct relation between the harmine concentrations and the jumping activity. This relation was observed in washed membranes in which about 40% of the harmine in whole homogenate was present. Tissue subfractionation showed that 30% of the harmine in whole brain homogenates was in the P2 fraction, and of this, 70% was located in the synaptosomes. The brain homogenate did not metabolize harmine and no metabolite was detected in the brain 10 min after treat ment with harmine and apomorphine.These results suggest that harmine itself, but not its metabolites, may be responsible for inducing the jumping behavior and that the jumping activity is correlated with brain harmine concentrations.

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Interactions of β-carbolines with the benzodiazepine receptor: Structure-activity relationships

Cited by 39 publications

References 9 publications

β-Carboline Alkaloids: Biochemical and Pharmacological Functions

β-Carboline Alkaloids: Biochemical and Pharmacological Functions

β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

Estimation of harmine and its derivatives by HPLC : Correlation of brain harmine levels with jumping behavior in rats.

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Interactions of β-carbolines with the benzodiazepine receptor: Structure-activity relationships

Cited by 39 publications

References 9 publications

&#946;-Carboline Alkaloids: Biochemical and Pharmacological Functions

&#946;-Carboline Alkaloids: Biochemical and Pharmacological Functions

β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

Estimation of harmine and its derivatives by HPLC : Correlation of brain harmine levels with jumping behavior in rats.

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β-Carboline Alkaloids: Biochemical and Pharmacological Functions

β-Carboline Alkaloids: Biochemical and Pharmacological Functions