Structure–activity studies of β-carbolines. 2. Crystal and molecular structures of N -ethyl-3-carbamoyl-β-carboline

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The crystal and molecular structures of methyl P-carboline-3-carboxylate, C13HIoN20, a high-affinity ligand for the benzodiazepine receptor, are reported. This candidate for the endogenous ligand for the receptor produces a biological response that is opposite to the anxiety-reducing effect of the usual agonists of the receptor and is, therefore, classified as an inverse-agonist. The space group is P2,/c with a = 11.4866(9), b = 5.8091(3), c = 32.417(3) A, P = 97.11 1(3)", Z = 8.In both of the unique molecules, the ester side chain has an extended conformation and is coplanar with the P-carboline moiety. The carbonyl oxygen atom and the aromatic nitrogen atom are cis and form a three-centre hydrogen bond to the amine nitrogen atom of the other molecule in the asymmetric unit.ALASTAIR K. S . MUIR et PENELOPE W. CODDING. Can. J. Chem. 63, 2752 (1985 On rapporte les structures cristalline et molkculaire du P-carbolinecarboxylate-3 de mkthyle, un ligand de grande affinitk pour le rkcepteur benzodiazkpine. Ce candidat pour le ligand endogkne pour le recepteur produit une reponse biologique qui est opposke a l'effet de rkduction d'anxiktk des agonistes usuels du recepteur; on peut donc le classifier comm? agoniste inverse. Methyl P-carboline-3-carboxylate (hereinafter CCM) is one of several P-carboline derivatives that have been studied as possible endogenous ligands for the benzodiazepine receptor (1). The identity of the natural ligand for the benzodiazepine receptor is not certain, as the isolation procedures from rat brain and from urine have been shown to chemically modify the naturally occumng P-carboline isolate to the ethyl ester. CCM binds with high affinity (2-4) to the receptor and displaces diazepam, an agonist. The P-carbolines produce three different responses when bound to the benzodiazepine receptor; the methyl ester is a convulsant (opposite to the agonists and hence labeled an inverse-agonist), the ethyl ester is a proconvulsant (potentiates the onset of convulsions), and the propyl ester acts as a weak agonist (anticonvulsant). ~r a e s t r u~e t al. (5) report that the binding of the P-carbolines and, hence, their effects are mediated by the inhibitory neurotransmitter, y-aminobutyric acid (GABA). The sensitivity of the binding of benzodiazepine receptor ligands to the presence of GABA has suggested an allosteric regulation of the GABA receptor by benzodiazepines (6). Recent models for this mechanism propose a multiconformation receptor; the different conformations are induced by' the binding of ligands of different biological effect (6, 7).These observations indicate the importance of the P-carbolines in the development of an understanding of the benzodiazepine receptor. The shapes and receptor binding characteristics of these molecules play an integral role in the biological response that they produce. The methyl ester has the highest affinity for the receptor of any of the P-carbolines that have been structurally characterized. The X-ray structure determination of CCM is part of an ongoing study...

Section: Discussionmentioning

confidence: 80%

“…The methyl ester has the highest affinity for the receptor of any of the P-carbolines that have been structurally characterized. The X-ray structure determination of CCM is part of an ongoing study of the ligands for this receptor (8). 'This paper has been presented in part: see Abstracts of the 13th International Congress of Crystallography, Acta Crystallogr.…”

mentioning

confidence: 99%

Structure–activity studies of β-carbolines. 3. Crystal and molecular structures of methyl β-carboline-3-carboxylate

Muir¹,

Codding²

1985

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“…, both esters show partial IT stacking which involves the A ring: Such interactions involving the A ring are postulated to be important to receptor binding (10,11). The only other type of IT-stacking observed in P-carboline crystals involved stacking of the side chain over the five-membered ring: this was observed for the low affinity N-ethyl-3-carbamoyl-P-carboline (24).…”

Section: Resultsmentioning

confidence: 99%

“…The trans conformati >n of the ester side chain that was found in the canthin-6-one cr..stal has also been observed in two non-ester benzodiazepin, receptor ligands: the N-ethyl-3-carbamoyl-P-carboline IV (24), which has low benzodiazepine receptor affinity (28), and 3-(methoxycarbony1)amino-pcarboline V (1 2), which produces 50% antagonism of diazepam (111) binding at a concentration of 71 nM (29). Because our examination (24) of the tabulated geometries of pyridyl-carbamoyl fragments showed that trans is the only observed conformation, and because the carbamoyl-P-carboline has low receptor affinity (28), we have proposed (24) that this trans conformation is not the binding conformation. Thus, models for the receptor-ligand interaction have assumed a cis conformation for the ester side chain (9, 13a, b).…”

Section: Discussionmentioning

confidence: 99%

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

Codding¹,

Szkaradzinska²,

Roszak³

et al. 1988

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. 66,2981 (1988).The crystal and molecular structures of two ligands for the benzodiazepine (BZ) receptor, t-butyl P-carboline-3-carboxylate, I (C16H16N202)r and 2-(methoxycarbonyl)canthin-6-one, I1 (C16HlaN203), are reported. The t-butyl P-carboline compound has high affinity for the receptor and is an antagonist; in contrast, the canthin-6-one has a 10-fold lower affinity for the receptor and no determinable in vivo activity. The space group for I is P2Jc with n = 11.756(1), b = 11.2324(8), c = 11.964(1) A, and P = 105.99(1)". For 11, the space group is also P21/c with n = 9.317(1), b = 7.964(1), c = 17.180(3) A, and P = 104.173 (7)". The orientation of the alkyl-carboxylate side chain is different in the two molecules and may be related to the difference in affinity and in vivo activity of the ligands. In addition, the packing arrangements in the two structures are dominated by T-stacking interactions; and, in the case of the t-butyl compound, by hydrogen bonding. On rapporte les structures cristallines et molCculaire de deux ligands du rCcepteur de la benzodiazepine (BZ) : la P-carboline carboxylate-3 de tert-butyle, I, (CI6Hl6N2O2) et la (methoxycarbony1e)-2 canthinone-6, 11, (C16HIONZ03) Le compose P-carboline de tert-butyle a une grande affinitC pour le rCcepteur et son antagoniste; la canthinone-6, au contraire a une affinit6 10 fois plus faible pour le ricepteuret son activit6 in vjvo n'est pas dCcelable. Le composC I appartient au groupe d'espace P2Jc avec [Traduit par la revue]

“…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%

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

Codding¹,

Roszak²,

Szkaradzinska³

et al. 1995

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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...