AMPA Receptors

AMPA receptor antagonists may modulate AMPA receptor function by acting at the glutamate recognition site (competitive antagonists) or at a distinct allosteric regulatory site for 2,3-benzodi-azepines (negative allosteric modulators). In addition, CA2+-permeable AMPA receptors can be antagonized by a diverse group of cationic channel blockers, including polyamines, spider and wasp toxins such as Joro spider toxin (JSTX), and IEM-1460. Recent and detailed reviews of AMPA-receptor structure, function, and pharmacology are available (7,91-93).

3.1.1. Competitive Antagonists

Competitive antagonists acting at the glutamate recognition site of AMPA receptors have shown promising neuroprotective, anticonvulsant, analgesic, and anxiolytic activities in animal models (92,93). Competitive antagonists also display beneficial effects upon certain stages of drug dependence (see subsequent chapters, this book). competitive AMPA-receptor antagonists include quinoxalinediones such as CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), NBQX [2,3-dihydroxy-6-nitro-7-sulfamoylbenzo (F)quinoxaline], and YM90K [6-(1H-imidazol-l-yl)-7-nitro-2,3-(1H-4#)-quinoxalinedione], as well as several structurally novel compounds including isatin oximes such as NS 257 {(1,2,3,6,7,8-hexahydro-3-(hydroxyimino)- N,N-[3H]dimethyl-7-methyl-2-oxobenzo[2,1-b:3,4-c']dipyrrole-5-sulfonamide} and decahydroisoquinolines such as LY293558 {(3S,4aR,6R,8aR)-6-[2-(1(2)H3-tetrazole-5-yl)ethyl] decahydroisoquinoline-3-carboxylic acid}. Most of these antagonists do not discriminate well between AMPA and kainate receptors (94). This is also the case for the water-soluble and systemically available isatin oxime NS 257, which not only blocks AMPA and kainate receptors but also interacts with NMDA receptors (95,96). NBQX, however, exhibits modest selectivity for AMPA-preferring receptors.

NBQX, like most other AMPA-receptor antagonists, generally produces motor and memory impairments in experimental animals at neuroprotective or anticonvulsant doses. However, in some cases therapeutic effects can be produced with little toxicity. For example, there is a good separation between the doses of NBQX that protect against cocaine-induced convulsions and those that induce motor impairment in mice (13). Moreover, NBQX attenuated both cocaine- and methamphetamine-induced locomotor stimulation in mice at doses that did not influence spontaneous locomotor activity (97). In addition, NBQX prevented the induction of sensitization to locomotor stimulant effects of cocaine (98) and CNQX blocked the reinstatement of cocaine self-administration induced by intra-accumbens AMPA or dopamine (99). NBQX did not substitute for the discriminative stimulus effects of dizocilpine, which may suggest that it is devoid of behavioral effects that are associated with NMDA-receptor antagonists (19).

Table 5

Some AMPA and Kainate Receptor Ligands

Compound Clinical status

Competitive AMPA Recognition-Site Antagonists CNQX NBQX

YM90K (YM900) YM872

ZK200775 (Fanapanel) NS-257 Ro 48-8587 LU 115455 LU 136541

Negative Allosteric AMPA Receptor Modulators GYKI 52466

LY 300164 (GYKI 53773; talampanel) Prior investigation—epilepsy, amyotrophic lateral sclerosis

LY 300168 (GYKI 53655) LY 303070 GYKI 47261 SYM 2206 SYM 2189

Positive Allosteric AMPA Receptor Modulators Aniracetam Piracetam CX516 Cyclothiazide Diazoxide S18986 IDRA-21

Kainate Receptor Antagonists NonSelective

NBQX, CNQX, DNQX NS-102 GluR5 Selective

LY 293558 (enantiomer of LY 215490) Clinical investigation—pain

LY 377770 (enantiomer of LY 294486) LY 382884 (enantiomer of LY 307130)

(Above GluR5-selective decahydroisoquinolines also block AMPA receptors LY 293558 >LY294486>LY 382884)

In humans NBQX, at low doses, was without significant effect on the electroencephalogram, body temperature, or cardiovascular function (100). In animal studies, YM90K demonstrates an improved pharmacokinetic profile in comparison with NBQX and is a potent neuroprotective and anticonvulsant agent (101). YM90K was tested in human healthy volunteers and appeared to be well tolerated, but its low solubility raises concerns (102). A series of compounds structurally related to YM90K but with improved selectivity for AMPA receptors have been synthesized (103,104). YM872 {2.3-dioxo-7-(1H-imidazol-1-yl)6-nitro-1,2,3,4-tetrahydro-1-quinoxal inyl]acetic acid} has improved solubility and a selectivity for AMPA receptors close to that of NBQX or YM90K (105). This compound displays remarkably potent neuroprotective effects after experimental ischemia in various species, is effective even when injected several hours following ischemia (106,107), and is also an effective analgesic (108).

Prior investigation—healthy volunteers (crystaluria) Prior investigation—stroke Clinical investigation—stroke Clinical investigation—stroke

In development—cognitive enhancer

Marketed (Europe)—cognitive enhancer

In development—cognitive enhancer, schizophrenia

LY293558 is a structurally distinct competitive antagonist that in addition to AMPA-receptor-blocking activity also has high affinity for GluR5 kainate receptors (109,110). LY 293558 has demon-stated neuroprotective, antinociceptive, and anticonvulsant activity (cf. ref. 111). In a number of experimental studies, LY 293558 showed beneficial effects on aspects of morphine addiction, including the development of sensitization (112) and tolerance (113) and on morphine-withdrawal signs (114). In clinical evaluation for experimental pain, LY 293558 had selective antihyperralgesic activity without significant effects on nociceptive stimuli in normal skin. LY 293558 did not produce neurological or cognitive deficits; however, mild and transient visual obscuration was observed after administration of a high dose of this compound (115).

New generations of competitive AMPA antagonists are now available, although chracterization of their effects in vivo is limited. For instance, Ro 48-8587 is a highly potent and selective AMPA antagonist (116). Compounds in a pyrrolyl-quinoxalinedione series (e.g., LU 115455, LU 136541) display more than a 1000-fold higher affinity at AMPA receptors than at kainate receptors and have shown efficacy against amygdaloid-kindled seizures at doses without motor impairing effects in rats (117). Another novel quinoxalinedione derivative, ZK200775, has greatly improved solubility and had a wide therapeutic window as a neuroprotective agent (118).

The overall efficacy of AMPA-receptor blockade (e.g., by NBQX) may be augmented synergisti-cally by low doses of NMDA-receptor antagonists without increasing adverse effects (119-121). LU 73068, which acts as an antagonist at the glycine site of NMDA receptors as well as an antagonist of AMPA receptors, is also an effective anticonvulsant agent in kindled rats with a more favorable therapeutic profile than either the AMPA antagonist NBQX or the glycine-site antagonist L-701,324 given separately (121).

3.1.2. Negative Allosteric Modulators

2,3-Benzodiazepines such as GYKI 52466 and its 3N-acetyl analog GYKI 53405 and 3N-methyl-carbamyl analog GYKI 53655 (LY300168) act as selective noncompetitive AMPA receptor antagonists (25,122-124) through negative allosteric modulation of AMPA receptor function (125,126). Like competitive AMPA receptor antagonists, these compounds posses a broad therapeutic potential in the treatment of conditions associated with excessive glutamate release, such as epilepsy, stroke, traumatic brain injury, and certain neurodegenerative disorders. (92,127). As noncompetitive antagonists, 2,3-benzodiazepines have the theoretical advantage that blockade would not be overcome by high synaptic glutamate levels (128). Interactions of 2,3-benzodiazepine derivatives with AMPA receptors are stereoselective, with activity residing in the minus isomers (e.g., LY 300164 and LY 303070), whereas the respective (+) isomers (e.g., LY 300165 and LY 303071) are devoid of AMPA receptor antagonistic properties (129). LY 300164 (GYKI 53773, talampanel) is orally available and has undergone clinical evaluation. It exhibited preliminary evidence of efficacy in epilepsy trials (phase II) and good tolerability, although high plasma concentrations were associated with ataxia, diplopia, sedation, and euphoria (92,93).

Recently, a variety of analogs of the original 2,3-benzodiazepines have been described that exhibit AMPA receptor-blocking activity and the possibility of reduced side effects. for example, several novel heterocyclic condensed and halogen-substituted 2,3-benzodiazepine derivatives such as GYKI 47261 have been shown to have good potency and broad anticonvulsant and neuroprotective activity comparable to GYKI 52466 and LY 300164 (130). In addition, a class of substituted 6,7-methylene-dioxy 1,2-dihydrophtalazines (SYM 2206, SYM 2207) that are closely related structurally to the 2,3-benzodiazepines also act as noncompetitive AMPA receptor antagonists with anticonvulsant and neuroprotective activity (131,132). Several 7-deoxygenated analogs have recently been reported to have similar AMPA-receptor-blocking activity, but one of these compounds, the 2-N-propylcarbamoyl SYM 2189, is said to have a higher protective index and longer duration of action than the other members of this class, although its overall in vivo potency is low in comparison with 2,3-benzodiazepines

(132). In contrast, a SYM 2207 analog having a ketone substituent [4-(4-aminophenyl)-6,7-methylene-dioxy-phthalazin-1(2#)-one] has 10-fold greater anticonvulsant potency than GYKI 52466, but a reduced toxicity profile and a longer duration of action (133). In in vitro studies, this analog is less potent than GYKI 52466 and GYKI 53655, suggesting that greater bioavailability accounts for its improved anticonvulsant potency.

Derivatives of methaqualone have also recently been shown to have very potent AMPA-receptor antagonist activity, although the selectivity and biological characterization of these compounds remains to be reported (134).

3.1.3. Positive Allosteric Modulators

Compounds that decrease the rate of desensitization or deactivation of AMPA receptors may enhance excitation mediated by the receptor and have novel therapeutic uses (e.g., in the treatment of cognitive disorders) (see refs. 91 and 135). Two main classes of positive modulators of the AMPA receptor can be distinguished: pyrrolidones (aniracetam, piracetam, and CX516) and benzothiadi-azides (cyclothiazide, diazoxide, S18986, and IDRA-21). Many of these AMPA receptor modulators including IDRA-21 (136,137) and CX516 (138,139) have been shown to improve performance of experimental animals in memory tasks. In both healthy volunteers (140) and elderly subjects, CX516 had significant beneficial effects on memory (144) without significant central or peripheral side effects. Positive allosteric modulators also have predicted therapeutic potential in schizophrenia based on the observation that schizophrenic patients have a reduced brain density of AMPA receptors in postmortem evaluation (see the review in ref. 142). Synergistic effects of CX516 and antipsychotic drugs were observed against methamphetamine-induced behavioral effects in rats, suggesting that this compound may be a useful adjuvant in treating schizophrenia (143); clinical trials are currently underway. However, given the potential for excitotoxicity or seizures with enhancement of glutamatergic neurotransmission, the use of these agents will need to be approached cautiously.

Thiocyanate ion is a negative allosteric modulator of AMPA receptors that acts by enhancing desensitization of the receptor (144). Recently, thiocyanate has been found to interact with the same site as the positive modulator cyclothiazide, and it can thus be considered an "inverse agonist" at this site (145). It should be noted that thiocyanate and cyclothiazide do not directly interact with the negative modulatory site for 2,3-benzodiazepines. Enhancement of AMPA-receptor desensitization is an intriguing potential therapeutic strategy that may permit inhibitory modulation of excessive gluta-matergic neurotransmission with reduced side effects (92). Thiocyanate could provide clues to the development of such inhibitory modulators.

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