Synthesis of substituted 7,12-dihydropyrido[3,2-b:5,4-b']diindoles: rigid planar benzodiazepine receptor ligands with inverse agonist/antagonist properties

Abstract

A series of 1-, 2-, 3-, 4-, 5-, 6-, 7-, 10-, and 12-substituted pyridodiindoles were synthesized and screened in vitro against [3H]diazepam for activity at the benzodiazepine receptor (BzR). In vitro, the 2-substituted pyridodiindoles were found to be the most potent (IC50 less than 10 nM) of this new class of BzR ligands. In vivo, 2-methoxypyridodiindole 19a (IC50 = 8 nM) was found to be the most potent partial inverse agonist (proconvulsant) of the series. The parent compound 2 (IC50 = 4 nM) was only slightly less potent. In addition, 2-hydroxypyridodiindole 21a (IC50 = 6 nM) was found to exhibit potent proconvulsant activity when administered as a prodrug derivative, pivaloyl ester 22. 2-Chloropyridodiindole 16a (IC50 = 10 nM) was devoid of preconvulsant activity; however, 16a was found to be the most potent antagonist of the anticonvulsant effects of diazepam in this class of BzR ligands. From the in vivo data available, substitution on ring E of 2 with electron-withdrawing groups results in antagonists at BzR, while replacement of hydrogen at C-2 with electron-releasing groups provides enhanced inverse agonist activity. The pyridodiindoles were used as "templates" for the formulation of a model of the inverse agonist/antagonist active site of the BzR. The proposed model consists of a hydrogen bond acceptor site (A1) and a hydrogen bond donor site (D2) disposed 6.0-8.5 A from each other on the receptor protein. The hydrogen-bonding sites are believed to be located at the base of a narrow cleft. A large lipophilic pocket at the mouth of the narrow cleft serves to direct molecules into the binding site, while the presence of a small lipophilic pocket permits substitution only at position 2 of the pyridodiindole nucleus for maximum binding potency.

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

“…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. Actually, the insertion of a methyl group in this position, as in (18)(19)(20)(21)(22), dramatically lowered efficacy, and with the exception of (18), showing a K i value of 860 nM, all the substituted compounds were devoid of any binding affinity. Within the (5-17) series, the presence of an aromatic ring in position 3 seemed mandatory for an appreciable efficacy, as both the 3-H derivative, (5), and the 3-CH 3 -substituted (6) showed no binding affinity.…”

“…(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.…”

“…In addition, novel, effective BzR ligands were emerging in literature, like the pyrazolo [4,3-c]quinolin-3-ones of Yokoyama 2)), [18], and the pyrido [3,2-b:5,4-b']diindoles of Cook and co-workers, ((4), Fig. (2)), [19], both characterized by rigid heteropolycyclic cores. As a consequence, considering that the great conformational flexibility of indolglyoxyl derivatives is a possible hindrance to a plain interaction with the BzR binding cleft, the authors setup a novel research programme devised to stiffen compounds (2) in a planar and cyclic cage, restricting their key pharmacophoric elements in a conformation fully complementary to the BzR site, in order to better control their binding affinities.…”

3-Arylisothiazoloquinols As Potent Ligands for the Benzodiazepine Site of GABA<sub>A</sub> Receptors

“…The model has recently been applied for the identification and optimization of novel 4-quinolones and azaflavone derivatives as ligands at the GABA A receptors, with affinities as low as 0.05 nM [9][10][11]. In addition, several other classes of compounds are known to bind to the benzodiazepine site, such as the 2-arylpyrazoloquinolines [12,13], -carbolines [14], pyridodiindoles [15], pyrimidin-5(6H)-ones [16], cyclopyrrolones and quinolines [17]. In the present investigation new azoloquinolones, 3-arylisothiazolo [5,4-b]quinolin-4(9H)-ones and 3-arylisoxazolo [5,4-b]quinolin-4(9H)-ones, have been designed using the pharmacophore model, prepared by synthesis, and assayed.…”

Synthesis and Pharmacological Evaluation of New 2-Substituted-5-{2-[(2-halobenzyl)thio)phenyl}-1,3,4-oxadiazoles as Anticonvulsant Agents

“…The BZD binding sites in the brain were identified and described by radioligand receptor binding assays and originally it was found that only 1,4-BZD derivatives bind to these receptors. It has since been shown that many groups of compounds bind to the BZD receptor with high affinity, e. g., triazolopyridazines, cyclopyrrolones, quinolines and β-carbolines [4][5][6][7]. Several pharmacophore models have been proposed for BZDs, and amongst all models suggested for binding to the BZD receptor at least two features are common: an aromatic ring and a coplanar proton accepting group in suitable distance (5A o ).…”