Structure and molecular modeling of GABAA receptor antagonists

Abstract

The recently described potent and selective GABAA antagonist SR 95531 (gabazine) is compared to six other GABAA antagonists: (+)-bicuculline, (-)-securinine, (+)-tubocurarine, iso-THAZ, R-5135, and pitrazepine. Starting from ab initio molecular orbital calculations performed on crystal atomic coordinates, attempts were made to identify in each structure the functional groups that are involved in receptor recognition and binding. A molecular modeling study revealed that (a) all compounds possess accessible cationic and anionic sites separated by an 4.6-5.2 A intercharge distance, (b) the antagonistic nature of the compounds can be explained by the presence of additional binding sites, (c) the correct spatial orientation of the additional binding sites is crucial for GABAA selectivity, and (d) the criteria determining the potency of the antagonist effect are an accurate intercharge distance (greater than 5 A) and the existence of hydrogen-bonding functionalities on one of the additional ring system. The presented pharmacophore accounts also for the inactivity of closely related compounds such as (-)-bicuculline, adlumidine, virosecurinine, allosecurinine, and the 4,6-diphenyl analogue of gabazine.

Dual mechanisms of GABAa response inhibition by β‐lactam antibiotics in the pyramidal neurones of the rat cerebral cortex

“…In addition, the nature and orientation of additional binding sites determine the selectivity and affinity for the GABAA receptor. The location in the elongation of the cationic site confers a higher selectivity for the GABAA receptor (Rognan et al, 1992 …”

Different Residues in the GABAA Receptor α1T60-α1K70 Region Mediate GABA and SR-95531 Actions

“…Most GABA A receptor agonists and antagonists contain a positively and a negatively charged functional group ϳ5 Å apart (41), similar to the GABA molecule. It is possible that these different classes of compounds bind with their intercharge portion in the same orientation.…”

Securinega Alkaloids from Flueggea leucopyra

“…13) Pharmacology investigations indicated that securinine was a stereospecific GABA A receptor antagonist with a significant central nervous system (CNS) activity. 14,15) In searching for bioactive alkaloids from the Euphorbiaceae plants, we had isolated some chemical constituents from Securinega suffruticosa and Flueggea virosa. 3,4) Flueggea leucopyra was a shrub which only distributed in Sichuan and Yunnan Provinces of China.…”

“…3 was isolated as yellow oil, and its HR-ESI-MS showed an [MϩH] ϩ ion peak at m/z: 266.1387 (Calcd for C 14 ] and a methoxy singlet (d H 3.27, s) were observed. The above data indicated that 3 was a dihydrosecurinine type alkaloid with a methoxyl group and a hydroxyl group.…”