3-Ethoxy-β-carboline: A high affinity benzodiazepine receptor ligand with partial inverse agonist properties

Trullás, Ramón; Ginter, Hillary; Jackson, Barrington; Skolnick, Phil; Allen, Michael S.; Hagen, Timothy J.; Cook, James M.

doi:10.1016/0024-3205(88)90208-1

Cited by 17 publications

(15 citation statements)

References 13 publications

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“…It was reported in 1974 by Hamaguchi et al 46 that the condensation of salicylaldehyde (43) with tryptophan methyl ester (17) in acidic media provided the Pictet-Spengler product 46 (Table 3, eq 2) as a mixture of the cis and trans isomers 46a,b, albeit in 3.5% overall yield. This same condensation carried out in benzene or toluene at reflux (Table 3, eq 1) provided only the imine 45.…”

Section: Introductionmentioning

confidence: 93%

The Pictet-Spengler condensation: a new direction for an old reaction

Cox¹,

Cook²

1995

Chem. Rev.

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938

460

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Section: Introductionmentioning

confidence: 93%

The Pictet-Spengler condensation: a new direction for an old reaction

Cox¹,

Cook²

1995

Chem. Rev.

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938

460

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“…The BZ inverse agonist 6,7-dimethoxy-4-ethyl-3-carbomethoxy--carboline (DMCM, 20) was reported to prevent lethality from overdoses of pentobarbital [133] and the 3-(hydroxymethyl)--carboline (3-HMC, 18) reduced pentobarbital-induced decrements in cerebral blood flow and oxygen consumption [134]. 3-Ethoxy--carboline was proven to be a potent, long-lived, water-soluble partial inverse agonist [135][136]. The DMCM (20) retains the highly convulsive nature of -CCM (17) in mice [137], while 6-(benzyloxy)-4-(methoxymethyl)-3-(ethoxycarbonyl)--carboline (ZK 93423, 21) differed significantly in its in vivo activity from -CCM (17) or DMCM (20) in that it is very similar to that of the agonist diazepam [139], and 5-(benzyloxy)-4-(methoxymethyl)-3-(ethoxycarbonyl)--carboline (ZK 91296, 22) represented the only known anticonvulsant -carboline derivative [138].…”

Section: Compounds Investigated Neuropharmacological Effectsmentioning

confidence: 99%

“…Inverse agonist [133] 2. Prevention lethality from overdoses of pentobarbital [133] 3-HMC Reduce of pentobarbital-induced decrements in cerebral blood flow and oxygen consumption [134] 3-Ethoxy--carboline Partial inverse agonist [135][136] ZK 93423 Agonist [139] ZK 91296 Anticonvulsant [138] 3-Ethylamino--carboline Proconvulsant activity in Papio papio baboons [79] -CMC Selectively antagonize the sedative effects of diazepam [79] FG 7142…”

Section: Compounds Investigated Neuropharmacological Effectsmentioning

confidence: 99%

β-Carboline Alkaloids: Biochemical and Pharmacological Functions

Cao

Peng²,

Wang³

et al. 2007

CMC

612

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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“…The discovery of high affinity, saturable, and stereospecific ligands for the BzR has been coupled with the demonstration that β-carbolines exhibited an affinity for the BzR 78–85. Some of these agents act on the BzR to induce effects that are functionally opposite (inverse agonists/antagonists) to those of classical BDZs.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and subtype selectivity of 3,6-disubstituted β-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse

Yin

Majumder

Clayton

et al. 2010

Bioorganic & Medicinal Chemistry

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A series of 3,6-disubstituted β-carbolines was synthesized and evaluated for their in vitro affinities at α x β 3 γ 2 GABA A /benzodiazepine receptor subtypes by radioligand binding assays in search of α 1 subtype selective ligands to treat alcohol abuse. Analogues of β-carboline-3-carboxylate-t-butyl ester (βCCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted β-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo βCCt (5). The bivalent ligands of βCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands. Based on the pharmacophore/receptor model, a preliminary SAR study on 34 analogues illustrated that large substituents at position -6 of the β-carbolines were well tolerated. As expected, these groups are proposed to project into the extracellular domain (L Di region) of GABA A /Bz receptors (see 32 and 33). Moreover, substituents located at position -3 of the β-carboline nucleus exhibited a conserved stereo interaction in lipophilic pocket L 1 , while N(2) presumably underwent a hydrogen bonding interaction with H 1 . Three novel β-carboline ligands (βCCt, 3PBC and WYS8), which preferentially bound to α1 BzR subtypes permitted a comparison of the pharmacological efficacies with a range of classical BzR antagonists (flumazenil, ZK93426) from several different structural groups and indicated these β-carbolines were "near GABA neutral antagonists". Based on the SAR, the most potent (in vitro) α 1 selective ligand was the 6-substituted acetylenyl βCCt (WYS8, 7). Earlier both βCCt and 3PBC had been shown to reduce alcohol selfadministration in alcohol preferring (P) and high alcohol drinking (HAD) rats but had little or no

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3-Ethoxy-β-carboline: A high affinity benzodiazepine receptor ligand with partial inverse agonist properties

Cited by 17 publications

References 13 publications

The Pictet-Spengler condensation: a new direction for an old reaction

The Pictet-Spengler condensation: a new direction for an old reaction

β-Carboline Alkaloids: Biochemical and Pharmacological Functions

Design, synthesis, and subtype selectivity of 3,6-disubstituted β-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse

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3-Ethoxy-β-carboline: A high affinity benzodiazepine receptor ligand with partial inverse agonist properties

Cited by 17 publications

References 13 publications

The Pictet-Spengler condensation: a new direction for an old reaction

The Pictet-Spengler condensation: a new direction for an old reaction

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

Design, synthesis, and subtype selectivity of 3,6-disubstituted β-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse

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β-Carboline Alkaloids: Biochemical and Pharmacological Functions