7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide (IDRA 21), a congener of aniracetam, potently abates pharmacologically induced cognitive impairments in patas monkeys.

Abstract

We report here on the ability of IDRA 21 and aniracetam, two negative allosteric modulators of glutamateinduced DL-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization, to attenuate alprazolam-induced learning deficit in patas monkeys working in a complex behavioral task. In one component of a multiple schedule (repeated acquisition or "learning"), patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four discriminative stimuli (geometric forms or numerals). In the other component (performance) the four-response chain was the same each session. In the central nervous system, y-aminobutyric acid (GABA) is the most important and abundant inhibitory neurotransmitter, acting at GABAA and GABAB receptors (1, 2). Glutamate is the most potent and abundant excitatory neurotransmitter, acting at ionotropic DL-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate, N-methyl-Daspartate receptors, and on metabotropic receptors (3). Together these two neurotransmitters maintain a fragile balance between neuronal excitation and inhibition. Regulation of such balance establishes a time-related association of functional neuronal assemblies and changes the strength of neuronal circuits (i.e., long-term potentiation) underlying various forms of learning and memory processes (4, 5), thereby establishing functional neuronal maps in the neocortex and the limbic system attending cognitive and sensory-motor function expression (6-8). Drugs that up-regulate GABAergic or downregulate glutamatergic transmission in neocortical and limbic brain areas produce dramatic sensory-motor and learning impairments (9-13). For example, a facilitation of GABAergic transmission elicited at specific GABA receptors by benzodiazepines acting as full or selective positive allosteric modulators (i.e., alprazolam, triazolam, or diazepam) or an inhibition of glutamatergic transmission elicited by competitive and noncompetitive inhibitors of glutamate action at N-methyl-Daspartate receptors (phencyclidine, dizocilpine, etc.) reduces acquisition and retention in rodents and in human and nonhuman primates (9-13). These considerations are central to the working model that neuropharmacologists have recently adopted in order to develop animal models to evaluate potency and efficacy of cognition-enhancing drugs acting through neocortical or limbic glutamatergic or GABAergic neurons (5, 9, 10, 13).In the past several years in our and others' laboratories, attention has been focused on allosteric modulatory sites located on GABAergic and glutamatergic receptors that might be targets for the action of drugs (i.e., partial allosteric modulators) improving neurological or neuropsychiatric disorders, including learning and memory abnormalities, without or with minimal adverse side effects (1,5,9,(10)(11)(12)14).A role for the negative allosteric modulation of glutamateinduced AMPA receptor desensitization in long-term potentiation and cognition ...

Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2

“…IDRA-21 has been demonstrated as a more potent AMPA receptor potentiator than the parent compound diazoxide [34]. In spite of a modest in vitro activity IDRA-21, but not CTZ, was found to be effective in vivo at enhancing cognition performance in animal models of cognitive impairments [19,35], making IDRA-21 a model compound for further developments. Even though IDRA-21 is unsuitable for ITC owing to low solubility combined with low affinity, it binds to the LBD in a similar manner to that of BPAM-97 ( Figure 2D).…”

The effects of huperzine A and IDRA 21 on visual recognition memory in young macaques

“…In previous studies, Thompson et al (1995) used a dose of 3 or 5.6 mg/kg to antagonise the effects of alprazolam in monkeys. In another study in monkeys (Buccafusco et al, 2004), the optimal dose of IDRA 21 for obtaining maximal performance improvement ranged between 0.3 and 10 mg/kg across animals, with an average of 1.9 mg/kg; this dose is comparable to the dose (2.5 mg/kg) used in our study.…”

“…In rats, it improved learning and memory in a spatial task (Uzunov et al, 1995; Zivkovic et al, 1995). Given orally to primates (patas monkeys), it blocked alprazolam-induced learning deficits in a complex behavioral task (Thompson et al, 1995). However, given to normal animals in the same experiment, it had no effect on the rate of learning, presumably because of a ceiling effect (Thompson et al, 1995).…”

AMPA Receptor Potentiators as Novel Antidepressants

“…Positive allosteric modulators include pyrollidone nootropics such as aniracetam, piracetam and oxyracetam and related compounds such as CX516 [31][32][33][34]. Other agents such as the benzothiadiazides, cyclothiazide, diazoxide and IDRA-21 [35][36][37] and PEPA [38] have also been described.…”