Structure-activity studies of β-carbolines. 4. Crystal and molecular structures of <i>t</i>-butyl β-carboline-3-carboxylate and 2-(methoxycarbonyl)canthine-6-one

Codding, Penelope W.; Szkaradzinska, M. B.; Roszak, A.W.; Aha, Lorraine J.; Hagen, Timothy J.; Cook, James M.

doi:10.1139/v88-463

Cited by 8 publications

(7 citation statements)

References 10 publications

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“…To this aim, the paper reports the crystal structures of four -carbolines, ZK93423 [3-carboethoxy-4-methoxymethyl-6-benzyloxy--carboline, fAG, (1)], ZK91296 [3-carboethoxy-4-methoxymethyl-5-benzyloxy-carboline, pAG, (2)], FG7142 [N-methyl-3-carbamoyl-carboline, IAG, (3)] and the low-af®nity ligand harmine hydrochloride [1-methyl-7-methoxy--carboline (4)]. This set of structural data is completed by the X-ray structures of other carbolines of known biological activity [DMCM (IAG: Bertolasi et al, 1990); Abecarnil (pAG: Bock et al, 1994); -CCM (IAG: Bertolasi et al, 1984); -CC t Bu (ANT: Codding et al, 1988), ZERHOT and ZERHUZ (ANT and IAG, respectively: Codding et al, 1995)] retrieved from the Cambridge Crystallographic Database (Allen, 2002) and by the structures of -CCE (IAG), 6-PBC (pAG) PRCC and ZK93426 (both ANTs), which, not being available as crystal structures, have been obtained by molecular±mechanics simulations. The structural features of all these molecules, which are summarized in (II), have been compared by superposition techniques and the structural comparison study is integrated by the Free± Wilson analysis (Free & Wilson, 1964) on 32 -carbolines of known binding af®nities data.…”

Section: Introductionmentioning

confidence: 99%

Structural features controlling the binding of β-carbolines to the benzodiazepine receptor

Ferretti¹,

Gilli²,

Borea³

2004

Acta Crystallogr Sect B

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Beta-carbolines are a class of drug which can interact with a high affinity with the benzodiazepine (BDZ) binding site of the GABAA receptor. The present paper, aimed at obtaining a deeper insight into the structure-properties relationships of this class of molecules, reports the crystal structures of four beta-carbolines: ZK93423 (3-carboethoxy-4-methoxymethyl-6-benzyloxy-beta-carboline), ZK91296 (3-carboethoxy-4-methoxymethyl-5-benzyloxy-beta-carboline), FG7142 (N-methyl-3-carbamoyl-beta-carboline) and the low-affinity ligand harmine hydrochloride (1-methyl-7-methoxy-beta-carboline). This set of structural data is completed by the X-ray structures of other carbolines of known biological activity retrieved from the Cambridge Crystallographic Database and by the structures of beta-CCE (3-carboethoxy-beta-carboline), 6-PBC (3-carboethoxy-4-methoxymethyl-6-isopropoxy-beta-carboline), PRCC (3-isopropoxy-beta-carboline) and ZK93426 (3-carboethoxy-4-methyl-5-isopropoxy-beta-carboline), which have been obtained by molecular-mechanics simulations. The structural features of all these molecules have been compared according to the stereochemical model we proposed in 1987. The structural comparison is integrated by the Free-Wilson analysis on 32 beta-carbolines of known binding affinity data.

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Section: Introductionmentioning

confidence: 99%

Structural features controlling the binding of β-carbolines to the benzodiazepine receptor

Ferretti¹,

Gilli²,

Borea³

2004

Acta Crystallogr Sect B

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“…4, both unique conformations of compound 1 form this hydrogen bond. The cis conformation of the sp2 hybridized N atom and the carbonyl oxygen atom facilitates formation of this three-center bond; this conformation is found in the crystal structures of most of the ester-containing BZD receptor ligands, regardless of the chemical type or the biological effect of the ligand (9,(11)(12)(13)(14). The ethoxy conformation that is observed in crystals of structure 3 could also facilitate a three-center hydrogen bond; the protonation of N (2) which show that a histidine residue is important for binding agonists and antagonist ligands.…”

Section: Discussionmentioning

confidence: 95%

“…Extensive crystallographic studies of P-carboline BZD receptor ligands (9,(11)(12)(13)(14) have identified three characteristic interactions and proposed that they are important for recognition. The crystal structures of compounds 1 , 2 , and 3 display these interactions.…”

Section: Discussionmentioning

confidence: 99%

“…Tables of atomic coordinates, bond lengths and angles, and the REFCODES have also been deposited with the Cambridge Crystallographic Data Centre, and can be obtained on request from The Director, Cambridge Crystallagraphic Data Centre, University Chemical Laboratory, 12 Union Road, Cambridge, CB2 lEZ, U.K.…”

Section: X-ray Crystallographymentioning

confidence: 99%

“…The structural features that favor binding of a P-carboline at the BZD receptor have been established (9)(10)(11)(12)(13)(14)(15). They include a planar, unsaturated ring system, a basic pyridyl N atom, an unobstructed indole N-H group, and at least one additional substituent: either (a) a side chain in position 3 that contains a carbonyl oxygen atom or is electron releasing, or (b) a hydrophobic group in position 5 or 6, or (c) an oxygen-containing side chain in position 4.…”

Section: Introductionmentioning

confidence: 99%

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Structure – activity relationships in antagonist and inverse agonist ligands for the benzodiazepine receptor

Codding¹,

Roszak²,

Szkaradzinska³

et al. 1995

Can. J. Chem.

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Abstract:The X-ray crystal and molecular structures of the three benzodiazepine (BZD) receptor ligands are presented and the electronic character of inverse agonist ligands is probed through molecular orbital calculations. Two of the ligands have a 6-benzylamino substituent: 6-benzylamino-p-carboline-3-carboxylic acid methyl ester, 1, which is a high affinity antagonist with IC,, = 10 nM, and 6-benzylamino-P-carboline, 2, which is a moderate affinity inverse agonist with IC,, = 106 nM. The third compound, 3-ethoxy-P-carboline hydrochloride, 3, displays partial inverse agonist activity with an IC,, of 24 nM. Intermolecular interactions, including extensive hydrogen bonding involving both the pyridyl nitrogen atom and the indole N-H as well as n stacking of aromatic rings, are characteristic of P-carbolines and are found in these three structures. In addition, two of these compounds are protonated in the crystalline state, thereby providing a model for interactions in the absence of the 3-carboxylic acid ester function. Electronic calculations show that (1) the partial inverse agonist ligand has the highest charge on the N(2) atom and (2) high affinity P-carbolines possess two neighboring sites that have high electrostatic attraction for a hydrogen atom in an intermolecular interaction. These findings suggest that modifications to the 3-position side chain to enhance the charge on the pyridyl N atom and provide a hydrogen bond acceptor site will facilitate the development of partial inverse agonist ligands.Key words: P-carbolines, benzodiazepine receptor, crystallography, structure-activity relationships.RCsumC : Faisant appel B la diffraction des rayons X, on a dCterminC les structures cristallines et moltculaires de trois coordinats rCcepteurs de benzodiazkpine (BDZ) et on a CvaluC le caractbre Clectronique des coordinats agonistes inverses B I'aide de calculs d'orbitales molCculaires. Deux des coordinats portent un substituant 6-benzylamino, soit I'ester mCthylique de l'acide 6-benzylamino-P-carboline-3-carboxylique (I), un antagoniste de grande affinitt avec IC,, = 10 nM, et la 6-benzylamino-P-carbonlin (2), un agoniste inverse d'affinitC modCree avec ICSo = 106 nM. Le troisikme composC, le chlorhydrate de la 3-Cthoxy-6-carboline (3), prCsente une activitC agoniste inverse partielle avec IC,, = 24 nM. Les interactions intermolCculaires, comprenant des ponts hydrogbnes importants impliquant I'atome d'azote du pyridyle ainsi que le N-H de l'indole de m&me que I'empilement n des noyaux aromatiques, sont caractCristiques des P-carbolines et on les retrouve dans les trois structures. De plus, deux de ces composCs, protonCs 2 I'ttat cristallin, peuvent servir de modbles pour les interactions en l'absence de la fonction ester de l'acide 3-carboxylique. Les calculs Clectroniques montrent que (1) le coordinat avec une activitt agoniste inverse partielle porte la charge la plus importante sur I'atome N(2) et (2) que les P-carbolines de plus grande affinitC possbdent deux sites voisins qui ont une grande attraction Clect...

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ChemInform Abstract: Structure‐Activity Studies of β‐Carbolines. Part 4. Crystal and Molecular Structures of tert.‐Butyl β‐Carboline‐3‐carboxylate and 2‐(Methoxycarbonyl)canthin‐6‐one.

et al. 1989

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Structure-activity studies of β-carbolines. 4. Crystal and molecular structures of t-butyl β-carboline-3-carboxylate and 2-(methoxycarbonyl)canthine-6-one

Cited by 8 publications

References 10 publications

Structural features controlling the binding of β-carbolines to the benzodiazepine receptor

Structural features controlling the binding of β-carbolines to the benzodiazepine receptor

Structure – activity relationships in antagonist and inverse agonist ligands for the benzodiazepine receptor

ChemInform Abstract: Structure‐Activity Studies of β‐Carbolines. Part 4. Crystal and Molecular Structures of tert.‐Butyl β‐Carboline‐3‐carboxylate and 2‐(Methoxycarbonyl)canthin‐6‐one.

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