Synthesis of novel 3-substituted .beta.-carbolines as benzodiazepine receptor ligands: probing the benzodiazepine receptor pharmacophore

Allen, Michael S.; Hagen, Timothy J.; Trudell, Mark L.; Codding, Penelope W.; Skolnick, Phil; Cook, James M.

doi:10.1021/jm00117a029

Cited by 84 publications

(112 citation statements)

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“…Methyl substitution at N(9) drastically reduces ligand affinity from IC,, = 5 nM for the P-carboline-3-carboxylic acid methyl ester (PCCM) to IC,, > 50 000 nM for its 9-methyl derivative (34), thereby suggesting the importance of this hydrogen bond. Even though the hydrogen-bonding patterns are quite different in the three structures reported here, in each case the indole N(9)-H participates in a hydrogen bond (see Table 4), which provides evidence that this group forms a hydrogen bond with the receptor.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

Codding¹,

Roszak²,

Szkaradzinska³

et al. 1995

Can. J. Chem.

Self Cite

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“…Series B contains 17 derivatives of b-carbolines with their observed affinities (Allen et al, 1988;Hollinshead et al, 1990;Sharma et al, 1992) and are reported in Table 2.…”

Section: Methodsmentioning

confidence: 99%

2D-QSAR of non-benzodiazepines to benzodiazepines receptor (BZR)

et al. 2008

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Several non-benzodiazepine compounds such as b-carbolines, imidazo-[1,2-a]-pyrimidines, and disubstituted purines bind with the benzodiazepine receptor site (BZR) with a high affinity. Thus, all compounds that bind to the BZR should have certain common characteristics that allow for recognition by the receptor regardless of the type of (in vivo) activity. Quantitative structure-activity relationships (QSAR) analyses of four series of non-benzodiazepines were carried out using different physicochemical descriptors. The molecular design and calculations were done by using ACD Lab software. For each set, 2048 regression models were generated and the best-fit model of each series was identified by using values of the coefficients q 2 and r 2 . In the case of the best-fit model of series A (r CV 2 = 0.82 r 2 = 0.86) and series C (r CV 2 = 0.91, r 2 = 0.97) the steric bulk interaction was dominant, whereas in the cases of series B (r CV 2 = 0.87, r 2 = 0.96) and series D (r CV 2 = 0.63, r 2 = 0.82) the electrostatic interaction was dominant.

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“…These ligands allosterically modulate the action of GABA on neuronal chloride ion flux, thus eliciting a wide variety of pharmacological actions ranging in a continuum from Bz-like action (full agonists with anxiolytic, sedative/hypnotic, and anticonvulsant activities) to Bz-opposed action (inverse agonists with proconvulsant and anxiogenic activities), via antagonists which do not exhibit any pharmacological effects per se, but can antagonize the action of both agonists and inverse agonists [1Ϫ4]. Among these compounds, the most interesting classes are β-carbolines I [5], pyrazoloquinolines II [6,7], triazolophthalazines III [8], and pyridodiindoles IV [9] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Benzodiazepine Receptor Affinity of Derivatives of the New Tricyclic Heteroaromatic System Pyrido[3′,2′:5,6]thiopyrano[4,3‐c]pyridazin‐3(2H,5H)‐one

Primofiore

Settimo

Marini

et al. 2005

Archiv der Pharmazie

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Derivatives 7-13 of a new tricyclic heteroaromatic system, pyrido[3',2':5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-one, were prepared as potential ligands at the benzodiazepine receptor, in view of their structural analogy with potent ligands such as the pyrazoloquinolines of the CGS series II, and especially with the benzothiopyrano[4,3-c]pyridazinones VI. They were obtained starting from the versatile ketones 2,3-dihydrothiopyrano[2,3-b]pyridin-4(4H)-one 1 and the corresponding 7-methyl derivative 2, via condensation with glyoxylic acid, and reaction of the intermediate acid mixtures with hydrazine or substituted phenylhydrazines. When evaluated for their binding affinity at the benzo diazepine receptor in bovine cortical membranes, the target compounds 8-13 displayed an affinity in the micromolar/submicromolar order. A hypothesis is presented to rationalize these results.

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Synthesis of novel 3-substituted .beta.-carbolines as benzodiazepine receptor ligands: probing the benzodiazepine receptor pharmacophore

Cited by 84 publications

References 5 publications

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

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

2D-QSAR of non-benzodiazepines to benzodiazepines receptor (BZR)

Synthesis and Benzodiazepine Receptor Affinity of Derivatives of the New Tricyclic Heteroaromatic System Pyrido[3′,2′:5,6]thiopyrano[4,3‐c]pyridazin‐3(2H,5H)‐one

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