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

Abstract

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...

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

“…The cis conformation of the ester side chain, which will enhance the proposed hydrogen bond formation between N(2) and the receptor by forming a three-center H-bond involving the carbonyl 0 atom as a secondary hydrogen acceptor, has been found in I and in another antagonist, 6-N-benzyl methyl ester (22) as well as in the inverse agonist esters (21,23), all high affinity ligands. The methoxycarbonyl amino P-carboline antagonist (l2), which crystallized with a trans side chain conformation, is shown to have an accessible cis conformation (vide infra); thereby supporting the hypothesized importance of the proposed cis interaction.…”

The molecular structure and conformational characteristics of some specific benzodiazepine receptor ligands: A molecular orbital study of C3-substituted betacarboline derivatives

“…The calculated structure parameters for BCCM are given in Table I for the two lowest energy conformers (planar structures, N2 trans or cis to 015), together with available crystal structure data [23,24]. The calculated structures of the most stable conformers of the other title molecules are collected in Table 11.…”

“…Both observations might have some bearing on the way BCs in general interact with, or activate, a receptor. According to present and both experimental [ 19, 23,24] and theoretical [ 1,18,25,26] knowledge about the BCs, the N2 nitrogen is quite sensitive to H-bonding. Extending this line of thought a bit further, we suggest that it could be worthwhile to investigate whether the N2-015-016 region of the BC esters might be involved in proton transfer from the receptor.…”

Molecular determinants of recognition and activation at GABAA/benzodiazepine receptors

“…However, their broad spectrum of activity and lack of specificity hinder the effectiveness of these compounds as drugs. With the ultimate goal of designing more behaviorally selective BDZ receptor ligands, several different pharmacophore models for the benzodiazepine receptors were developed in our own laboratory 7–11 as well as from other research groups 12–26 during the past 15 years. Most of these models use a large number of structurally diverse BDZ receptor ligands to explain ligand efficacy as a function of ligand–receptor interaction at the molecular level.…”