Synthesis, Structure−Activity Relationships, and Molecular Modeling Studies of N-(Indol-3-ylglyoxylyl)benzylamine Derivatives Acting at the Benzodiazepine Receptor^,

Abstract

A number of N-(indol-3-ylglyoxylyl)benzylamine derivatives were synthesized and tested for [3H]flunitrazepam displacing activity in bovine brain membranes. Some of these derivatives (9, 12, 14, 15, 17, 27, 34, 35, 38, 41, and 45) exhibited high affinity for the benzodiazepine receptor (BzR) with Ki values ranging from 67 to 11 nM. The GABA ratio and [35S]-tert-butylbicyclophosphorothionate binding data, determined for the most active compounds, showed that they elicit an efficacy profile at the BzR which depends on the kind of substituent present on the phenyl ring of the benzylamine moiety. Moreover, lengthening (propylamine derivatives 1-3) and shortening (aniline derivatives 46-54) of the distance between the phenyl ring and the amide group of the side chain gave compounds with a drastically lower binding potency. The biological results are discussed in the light of a recently proposed pharmacophore model and compared, by molecular modeling studies, with those obtained from effective BzR ligands.

Geometrically Constrained Analogues of N‐Benzylindolylglyoxylylamides: [1, 2, 4]Triazino[4, 3‐a]benzimidazol‐4(10H)‐one Derivatives as Potential New Ligands at the Benzodiazepine Receptor

“…The benzylamine derivatives 1-3 demonstrated a potency lower than that of the corresponding N-benzylindolylglyoxylylamides II, which present K i values ranging from 52 to 120 nM [10]. The most potent compound was 1, characterized by an unsubstituted phenyl on the side chain, which showed a K i value of 1 µM.…”

“…We have recently reported a new class of potent BzR ligands, the N-(arylalkyl)indolylglyoxylylamides II (Chart 1); these are hypothesized to assume a pseudoplanar arrangement mimicking the β-carbolines I (Chart 1) [8], which are high affinity ligands at the BzR [9,10]. The most active indole derivatives are those featuring a benzylamine residue (n = 1) in the side chain, with K i values in the nanomolar range [10].…”

“…The most active indole derivatives are those featuring a benzylamine residue (n = 1) in the side chain, with K i values in the nanomolar range [10]. In search for rigid analogues of II, we have disclosed a series of potent BzR Scheme 1.…”

The use of a pharmacophore model for identification of novel ligands for the benzodiazepine binding site of the GABAA receptor

“…If the search in ACD and Maybridge is repeated with the more constrained pharmacophore the result is 8 hits (Scheme 3) and compound 39 and 40 are among these. Compound 45 belongs to a class of compounds which have affinity to the benzodiazepine binding site [39][40][41]. Compounds 44, 46-49 could not be purchased.…”

Novel N-Substituted Indol-3-ylglyoxylamides Probing the LDiand L1/L2Lipophilic Regions of the Benzodiazepine Receptor Site in Search for Subtype-Selective Ligands

“…19 However, the factors determining R 2 selectivity are not so clearly defined, as the same research group subsequently proposed that a BzR ligand which potently interacts with the L Di region displays R 1 selectivity, despite occupation of other receptor lipophilic areas. 17,18 Taking the benzylindolylglyoxylamides Ia and Ib as reference compounds (Table 1), 14 we decided to probe the steric recognition properties of the L Di and L 2 pockets in two different ways: by varying the substituent on the benzylamide phenyl ring (compounds 10-23 in Table 1) or by replacing the benzyl moiety with alkyl groups (compounds 24-37 in Table 1). This paper describes the synthesis, biological evaluation, and SARs of the new indole derivatives 10-37.…”