N‘-Phenylindol-3-ylglyoxylohydrazide Derivatives:  Synthesis, Structure−Activity Relationships, Molecular Modeling Studies, and Pharmacological Action on Brain Benzodiazepine Receptors

Abstract

A series of N'-phenylindol-3-ylglyoxylohydrazides, isosters of the N-benzylindol-3-ylglyoxylamide derivatives previously described by us, were synthesized and tested for their ability to displace [3H]Ro 15-1788 from bovine brain membranes. These compounds were designed with the aim of obtaining products which could exert an in vivo activity, thanks to a higher hydrosolubility and consequently a better bioavailability. Affinity was restricted to the derivatives unsubstituted in the 5 position of the indole nucleus (1, 6, 9, 12, 15, 18, 23, and 26), with Ki values ranging from 510 to 11 nM. The most active compounds (6, 9, 23, and 29) proved to be effective in antagonizing pentylenetetrazole-induced seizures. Molecular modeling studies were performed to rationalize the lack of affinity of hydrazides with a chloro or a nitro group in the 5 position of the indole nucleus. It was hypothesized that the conformational preference of the hydrazide side chain, characterized by a gauche disposition of lone pairs and substituents about the N-N bond, prevents all hydrazides from binding to the receptor similarly to other classes of indole analogues previously investigated. The potency of 5-H hydrazides was attributed to a binding mode which is not feasible for 5-Cl and 5-NO2 counterparts. This theoretical model of ligand-receptor interaction permitted a more stringent interpretation of structure-affinity relationships of hydrazides and of recently described benzylamide derivatives (Da Settimo et al. J. Med. Chem. 1996, 39, 5083-5091).

Geometrically Constrained Derivatives of Indolylglyoxylamides as Ligands Binding the GABAA/BzR Complex

“…(4). Different substitution patterns were explored in positions 3 of the heterocyclic core, (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), and some of them were combined with methylation at position 10, (18)(19)(20)(21)(22), to deduce some useful SARs for this novel class of rigid BzR ligands. Binding affinity studies at the BzR, performed in bovine brain membranes through displacement experiments with the radiolabelled antagonist [ 3 H]Ro 15-1788, (Table (1)), clearly emphasized the key pharmacophoric role of the N(10)-H group, postulated as a hydrogen bond donor site.…”

“…Indeed, as time passed and a growing body of evidence demonstrated the key role of GABA A /BzR complex in modulating the degree of anxiety-related emotional disorders, the state of vigilance and the likelihood of convulsions, the development of specific ligands became a major pharmaceutical challenge. As more definite knowledge about the receptor binding cleft was acquired, Da Settimo and co-workers modified compounds (2) accordingly, to satisfy increasingly structural and pharmacophoric requirements of BzR ligands [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. In particular, keeping the indole nucleus and the glyoxyl bridge constant, they explored different substitution patterns on both position 5 of the nucleus and the 3-glyoxyl side chain.…”

GABAand Glutamate Receptor Ligands and their Therapeutic Potential inCNSDisorders

“…The model is based on 136 different ligands from 10 structurally different classes of compounds. This model has been widely used for the design of novel ligands [180,181] and for SAR analyses [182][183][184]. The elements of the pharmacophore model are shown in Figure 14.…”

“…A number of decahydroisoquinoline-based acidic amino acids, including LY382884 (181), has been characterized as competitive GluR5selective antagonists that exhibit antinociceptive effects [391]. One example is BSF 91594 (183), which shows more than 50-fold selectivity for GluR5 over other KA receptor subtypes or AMPA receptors. In addition, a group of quinoxalinedione-derived antagonists structurally related to the AMPA receptor antagonist 157 (Fig.…”

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.…”