Molecular yardsticks. Rigid probes to define the spatial dimensions of the benzodiazepine receptor binding site

Abstract

A series of rigid planar azadiindoles (8a, 8b, and 8d), benzannelated pyridodiindoles (11a, 11b, and 11d), and indolopyridoimidazoles (11c, 20, and 24) were synthesized from 4-oxo-1,2,3,4-tetrahydro-beta-carboline 5 via the Fischer indole cyclization with the appropriate arylhydrazines. These analogues were employed as probes ("molecular yardsticks") to define the spatial dimensions of the lipophilic regions of the benzodiazepine receptor (BzR) binding cleft. Benzannelated indoles 11a-d and indolopyridoimidazoles 20 and 24 were important in establishing an area of negative interaction (S1, see Figure 6, part b) in the binding cleft common to the interactions of both inverse agonists and agonists. Data from this chemical and computer-assisted analysis of the pharmacophore (see Figure 6) indicates that inverse agonists and agonists bind to the same binding region, but the pharmacophoric descriptors required for the two activities are different, in keeping with previous studies with these planar ligands. However, the hydrogen bond donating site H1 and the lipophilic region L1 in the receptor binding site are common interactions experienced by both series of ligands. The low affinities of both indolo[3,2-c]carbazole (3a) and indolo[3,2-b]isoquinoline (3b) for the BzR are consonant with the requirements of a hydrogen bond acceptor interaction at donor site H1 and a hydrogen bond donor interaction at acceptor site A2 for potent inverse agonist activity in the beta-carboline series. The hydrochloride salts of 1-aza- 8a (IC50 10.6 nM), 2-aza- 8b (IC50 51.5 nM), and 4-azadiindole 8d (IC50 11.2 nM) were found to be much more soluble in water than the corresponding salt of the parent diindole 2. Moreover, aza analogues 8a and 8b were shown to be partial inverse agonists with proconvulsant potencies comparable to that of the parent diindole 2.

Two Annulated Azaheterocyclic Cores Readily Available from a Single Tetrahydroisoquinolonic Castagnoli–Cushman Precursor

“…Starting from HPA, compound 11 was prepared in an overall yield of 40%, over 4 steps (see Supplementary material). This is in sharp contrast to the previously reported synthetic routes to 11 (8% over 4 steps [35] or 12% over 5 steps [36]). Another advantage of the new route to compound 11 presented herein contrasting it to the previously reported approaches [33,34] is its being free from the use of palladium catalysts, which is an obvious upside from the standpoint of pharmaceutical production [37].…”

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

“…Figure shows the superimposed molecular models of hydrazide 23 (adopting binding mode B) and of the benzopyridodiindole III , reported to be much less potent than pyridodiindole I . The fused benzene ring F of III has been claimed to disrupt binding through an unfavorable steric interaction with the receptor region S 2 . , Notice that the 5 position of 23 points toward ring F of III . This suggests that alignment B is not feasible for 5-substituted hydrazides, due to a steric clash between the 5-Cl or 5-NO 2 group and the S 2 site (see also Figure ).…”

Neuroactive Flavonoids Interacting with GABAA Receptor Complex

“…Further investigation into the subtype selectivity of these flavonoids would lead to deeper understanding in both the interaction modules of the BZ-site that govern the efficacies amongst the class of compounds and also the specific behavioral regulation of each BZ-site subtype. The enormous amount of SAR data available for a diversity of ligands has resulted in the formulation of several pharmacophore models for the BZ-site [74][75][76][77][78][79][80][81][82]. A comprehensive model of the pharmacophore for agonist, antagonist and inverse agonist at the BZ-site has been proposed by Cook and co-workers [83].…”