Search

Positive allosteric modulators of gamma-aminobutyric acid (GABA)A receptors, including benzodiazepines and congeners, can be classified into three categories: 1) full allosteric modulators (i.e., triazolam and alprazolam) that act with high potency and efficacy at many GABAA receptors; 2) selective allosteric modulators (i.e., diazepam) that act with high potency and high efficacy at selected GABAA receptors; and 3) partial allosteric modulators (i.e., bretazenil) that act with high potency but low efficacy at many GABAA receptors. Imidazenil, an imidazobenzodiazepine carboxamide, has been characterized as a novel representative of the partial allosteric modulator class. When tested on a broad spectrum (native and recombinant) of GABAA receptors, imidazenil positively modulates the GABA-elicited Cl- currents with a 4- to 5-fold higher potency but an efficacy (30-50%) lower than that of diazepam, and it antagonizes the effects of the latter drug. Imidazenil in vitro (Ki = 5 x 10(-10) M) and in vivo (ID50 = 0.2 mumol/kg i.v.) displaces [3H]flumazenil from its brain binding sites and in vivo it possesses a marked anticonflict profile in the rat Vogel conflict-punishment test and is 10 times more potent than bretazenil and 100 times more potent than diazepam or alprazolam in antagonizing bicuculline- and pentylenetetrazol-induced seizures. Unlike diazepam and alprazolam, which induce sedation and ataxia and potentiate the effects of ethanol and thiopental at doses similar to those that produce anticonflict effects and occupy 50% of brain flumazenil binding sites, imidazenil does not produce ataxia or sedation in rats nor does it potentiate the effects of ethanol or thiopental in doses 30- to 50-fold higher than those required for the anticonflict effect and for 100% occupancy of brain flumazenil binding sites. Furthermore, when administered with diazepam, imidazenil blocks in a dose-related fashion the sedative, ataxic effects of this drug and thus acts on these unwanted responses as an antagonist (i.e., like flumazenil). In all tests, imidazenil has the pharmacological profile of a partial allosteric modulator, but is more potent than bretazenil, has a longer biological half-life and, in rodents, is virtually unable to cause sedation, ataxia or to potentiate ethanol toxicity.

The 2 aryl-3-indoleacetamides (FGIN-1) are a new class of compounds that potently (nM) and selectively bind to glial mitochondrial diazepam binding inhibitor (DBI) receptors (MDR), previously called peripheral benzodiazepine receptors, and increase mitochondrial steroidogenesis. The high-affinity binding of FGIN-1 to MDR derivatives depends on the following chemical characteristics: 1) the dialkylation of the amide; 2) the chain length of this alkyl substitution; and 3) the halogenation of aryl groups appended to the indole nucleus. FGIN-1 derivatives do not bind to gamma-aminobutyric acid (GABAA), GABAB, glycine, glutamate, dopamine, serotonin, opiate, cholecystokinin, beta adrenergic, cannabinoid or sigma receptors. FGIN-1-27 [N, N-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide] enters the brain, and for this reason, this FGIN-1 compound is potent and efficacious behaviorally. Like the neurosteroid 3 alpha-5 alpha tetrahydrodeoxycorticosterone (THDOC), FGIN-1-27 delays the onset of isoniazid-induced convulsions, but fails to delay the onset of bicuculline-induced convulsions. However, differently from THDOC, the FGIN-1-27 anticonvulsant action is blocked by the isoquinoline carboxamide PK 11195. In the elevated plus maze test, FGIN-1-27 inhibits neophobia manner that is antagonized by PK 11195 but not by flumazenil. Because FGIN-1-27 binds to MDR and does not bind to the GABAA receptors, it is inferred that FGIN-1-27 may act on GABAA receptors indirectly, presumably via a stimulation of neurosteroid synthesis and release from glial cells.

gamma-Aminobutyric acid (GABA)-activated Cl- currents in neonatal rat cortical neurons and in cultured cells engineered for the expression of specific molecular forms of the GABAA receptor alpha, beta, and gamma subunits, were recorded with the patch-clamp technique in the whole-cell configuration. The effects of various allosteric modulators of GABAA receptors were determined. Diazepam and clonazepam showed greater efficacy as positive modulators of GABA-elicited currents in alpha 2 beta 1 gamma 2 or alpha 3 beta 1 gamma 2 receptors than in alpha 1 beta 1 gamma 2 or alpha 5 beta 1 gamma 2 receptors or in cortical neurons. Alpidem was more efficacious at alpha 1 beta 1 gamma 2 or alpha 2 beta 1 gamma 2 receptors than at alpha 1 beta 1 gamma 2 or alpha 5 beta 1 gamma 2 receptors or in cortical neurons. Conversely, zolpidem was equally efficacious for all these receptors except for alpha 5 beta 1 gamma 2. Both imidazopyridines (alpidem and zolpidem) were virtually ineffective at modulating the GABA response of alpha 5 beta 1 gamma 2 receptors and in almost all the receptors assembled from alpha 1, alpha 2, alpha 3 or alpha 5 subunits together with beta 1 and gamma 1 subunits. The beta-carboline derivatives methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and methyl-beta-carboline-3-carboxylate (beta-CCM) elicited a positive allosteric modulation of alpha 1 beta 1 gamma 1 or alpha 2 beta 1 gamma 1 receptors, whereas they acted as negative allosteric modulators at nearly all other receptors tested, as they do in cortical neurons. Although the positive allosteric modulation by beta-carbolines never exceeded a doubling of the GABA response, DMCM was more efficacious at alpha 1 beta 1 gamma 1 receptors and beta-CCM was more efficacious at alpha 2 beta 1 gamma 1 receptors. DMCM was inactive at alpha 3 beta 1 gamma 1 receptors, whereas beta-CCM was virtually inactive at alpha 5 beta 1 gamma 1 receptors. The benzodiazepine 4'-chlorodiazepam, which is a negative modulator resistent to flumazenil inhibition, acted at all the various GABAA receptors that contained a gamma subunit.