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

Abstract

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.

Retracted: Addition of a single methyl group to a small molecule sodium channel inhibitor introduces a new mode of gating modulation

“…The enantiomer dependent effects of DPI 201–106 are reminiscent of the voltage dependent calcium channel inhibition/activation elicited by enantiomers of dihydropyridines (Hockerman et al ., ; Natale and Steiger, ), which have been reported to result from interactions with the homologous domains 3 and 4 S5 and S6 transmembrane helices that form the pore (Peterson et al ., ; Hockerman et al ., ; Schleifer, ). Similar inhibition/activation switching has been reported for modulators of the Trp channel TRPA1 and potassium channels as well as agonist/inverse agonists of GABA receptor channels (Ferretti et al ., ; Defalco et al ., ; Banzawa et al ., ). Interestingly, a recent study has reported that addition of a single methyl group to the non‐selective Kv7.2‐7.5 opener (S)‐2 converts it to a subtype selective inhibitor/opener (Blom et al ., ).…”

Bis(6-methoxy-1-methyl-2,3,4,9-tetrahydro-1H-β-carbolin-2-ium) tetrachloridozincate(II) dihydrate

“…For structures of -carboline and related compounds, see: Anlong et al (2007); Larghi et al (2005); Reimers et al (1984); Wouters (1997); Ferretti et al (2004). For a related tetrachloridozincate structure, see: Ma et al (2009).…”

An Updated Unified Pharmacophore Model of the Benzodiazepine Binding Site on γ-Aminobutyric Acida Receptors: Correlation with Comparative Models

“…The crystal structures and molecular mechanics simulations of several -carbolines has recently been reported [83]. In general, substitution at C(3) and C(6) had the greatest effect on affinity.…”