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PubMed1991

Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor.

The N-methyl-D-aspartate (NMDA) receptor is believed to play a major role in learning and in excitotoxic neuronal damage associated with stroke and epilepsy. Pregnenolone sulfate, a neurosteroid, specifically enhances NMDA-gated currents in spinal cord neurons, while inhibiting receptors for the inhibitory amino acids glycine and gamma-aminobutyric acid, as well as non-NMDA glutamate receptors. This observation is consistent with the hypothesis that neurosteroids such as pregnenolone sulfate are involved in regulating the balance between excitation and inhibition in the central nervous system.

Allosteric Regulation↗
PubMed2003

Positive allosteric modulators of AMPA receptors are neuroprotective against lesions induced by an NMDA agonist in neonatal mouse brain.

Four positive modulators of AMPA-type glutamate receptors (cyclothiazide, CX614, LY404187 and S18986-1) given in acute or chronic manner exerted a neuroprotective effect in lesions induced in postnatal day 5 (P5) mice by intracerebral injection of ibotenate, an NMDA agonist. The neuroprotective effects were mediated via the MAPK pathway since coinjection of the MEK inhibitor, PD98059, blocked the neuroprotective effects. Administration of CX614 to neonatal mice was followed by upregulation of hippocampal and cortical BDNF expression.

Allosteric Regulation↗
PubMed2004

Interactions of allosteric modulators of AMPA/kainate receptors on spreading depression in the chicken retina.

The functional role of AMPA and kainate receptors in spreading depression (SD) was investigated in the isolated chicken retina. Competitive (NBQX) and non-competitive (GYKI 52466, GYKI 53405 and GYKI 53655) antagonists of the AMPA receptor inhibited AMPA-induced SD in a concentration-dependent manner. Concentrations of drugs caused 50% inhibition (IC(50) values) are 0.2, 16.6, 7.0 and 1.4 microM, respectively. AMPA receptor positive modulator cyclothiazide was more effective in the potentiation of SD evoked by AMPA than by kainate. Slight potentiation of either AMPA- or kainate-induced SD was observed only at high concentration (1 mg/ml) by the kainate receptor modulator concanavalin A. Compounds that positively modulate AMPA receptor function (cyclothiazide, IDRA-21, S 18986, 1-BCP and aniracetam) caused a concentration-dependent potentiation in SD. Concentrations of drugs that caused 50% potentiation (estimated EC(50) values) are 9, 135, 142, 450 and 1383 microM, respectively. Interaction between cyclothiazide, aniracetam or S 18986 administered with each other, or with GYKI 52466, respectively, was also investigated. When cyclothiazide and S 18986 were co-applied, their effects seemed to be additive. However, lack of additivity was obtained when S 18986 was added together with aniracetam. Positive modulators applied at equiactive concentrations reduced the inhibitory action of GYKI 52466 and differently shifted its concentration-response curve. In this respect, S 18986 was the most effective (IC(50) of GYKI 52466 changed from 16.6 to 51.9 microM). Our findings indicate the contribution of AMPA rather than kainate receptors in the mediation of retinal spreading depression. Our data further support the idea that multiple positive modulatory sites are present on the AMPA receptor complex in addition to a negative modulatory site.

Allosteric Site↗
PubMed2002

Kainate receptor agonists, antagonists and allosteric modulators.

Interest in kainate receptors has increased over the past few years. Our understanding of their physiology and pharmacology has improved markedly since their original cloning and expression in the early 1990s. For example, agonist profiles at recombinant kainate receptors have been used to identify and distinguish kainate receptors in neurons. Furthermore, the development of selective antagonists for kainate receptor subtypes has increased our understanding of the functional roles of kainate receptors in neurons and synaptic transmission. In this review we described the activity of agonists and antagonists at kainate receptors and their selectivity profiles at NMDA and non-NMDA receptors.

Allosteric Regulation↗
PubMed2002

Negative allosteric modulation of AMPA-preferring receptors by the selective isomer GYKI 53784 (LY303070), a specific non-competitive AMPA antagonist.

GYKI 53784 or LY303070 [(-)1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3-methylcarbamoyl-2,3-benzodiazepine] belongs to a new family of 2,3-benzodiazepine compounds (also called homophtalazines) selective and non-competitive antagonists at alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. These compounds include the original GYKI-52466, its more potent derivative GYKI 53655 and the active isomer of the latter, GYKI 53784. This review summarizes current knowledge of this novel AMPA antagonist: GYKI 53784. GYKI 53784 is the most potent of the compounds in the 2,3-benzodiazepine class, blocking AMPA receptor-mediated responses. In contrast to the compounds of the quinoxalinedione family, that block AMPA as well as kainate receptors, GYKI 53784 does not block the activation of kainate receptors. Furthermore, GYKI 53784 does not act at the same receptor site as positive AMPA modulators (i.e., cyclothiazide, BDP-12, 1-BCP or aniracetam). GYKI 53784 is a powerful neuroprotective agent in both in vitro and in vivo models of AMPA receptor-mediated excitotoxicity. In contrast to NMDA receptor antagonists, whose favorable clinical actions are compromised by important side effects such as the impairment of memory functions, the selective AMPA antagonist, GYKI 53784, may be of potential clinical value, both in acute (stroke and trauma) and chronic (Alzheimer's disease, epilepsy) neurological disorders.

Action Potentials↗
PubMed2004

The heptahelical domain of GABA(B2) is activated directly by CGP7930, a positive allosteric modulator of the GABA(B) receptor.

The gamma-aminobutyric acid, type B (GABA(B)) receptor is well recognized as being composed of two subunits, GABA(B1) and GABA(B2). Both subunits share structural homology with other class-III G-protein-coupled receptors. They are composed of two main domains: a heptahelical domain (HD) typical of all G-protein-coupled receptors and a large extracellular domain (ECD). Although GABA(B1) binds GABA, GABA(B2) is required for GABA(B1) to reach the cell surface. However, it is still not demonstrated whether the association of these two subunits is always required for function in the brain. Indeed, GABA(B2) plays a major role in the coupling of the heteromer to G-proteins, such that it is possible that GABA(B2) can transmit a signal in the absence of GABA(B1). Today only ligands interacting with GABA(B1) ECD have been identified. Thus, the compounds acting exclusively on the GABA(B2) subunit will be helpful in analyzing the specific role of this subunit in the brain. Here, we explored the mechanism of action of CGP7930, a compound described as a positive allosteric regulator of the GABA(B) receptor. We showed that it activates the wild type GABA(B) receptor but with a low efficacy. The GABA(B2) HD is necessary for this effect, although one cannot exclude that CGP7930 could also bind to GABA(B1). Of interest, CGP7930 could activate GABA(B2) expressed alone and is the first described agonist of GABA(B2). Finally, we show that CGP7930 retains its agonist activity on a GABA(B2) subunit deleted of its ECD. This demonstrates that the HD of GABA(B2) behaves similar to a rhodopsin-like receptor, because it can reach the cell surface alone, can couple to G-protein, and be activated by agonists. These data open new strategies for studying the mechanism of activation of GABA(B) receptor and examine any possible role of homomeric GABA(B2) receptors.

Allosteric Regulation↗
PubMed2005

Allosteric modulation of anti-HIV drug and ferric heme binding to human serum albumin.

Human serum albumin (HSA), the most prominent protein in plasma, is best known for its exceptional capacity to bind ligands (e.g. heme and drugs). Here, binding of the anti-HIV drugs abacavir, atazanavir, didanosine, efavirenz, emtricitabine, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, stavudine, and zidovudine to HSA and ferric heme-HSA is reported. Ferric heme binding to HSA in the absence and presence of anti-HIV drugs was also investigated. The association equilibrium constant and second-order rate constant for the binding of anti-HIV drugs to Sudlow's site I of ferric heme-HSA are lower by one order of magnitude than those for the binding of anti-HIV drugs to HSA. Accordingly, the association equilibrium constant and the second-order rate constant for heme binding to HSA are decreased by one order of magnitude in the presence of anti-HIV drugs. In contrast, the first-order rate constant for ligand dissociation from HSA is insensitive to anti-HIV drugs and ferric heme. These findings represent clear-cut evidence for the allosteric inhibition of anti-HIV drug binding to HSA by the heme. In turn, anti-HIV drugs allosterically impair heme binding to HSA. Therefore, Sudlow's site I and the heme cleft must be functionally linked.

Allosteric Regulation↗
PubMed1982

Morphine allosterically modulates the binding of [3H]leucine enkephalin to a particulate fraction of rat brain.

Equilibrium binding studies have demonstrated that [3H]leucine enkephalin labels a single class of binding sites in a particulate fraction of rat brain with a dissociation constant (KD) of 3.2 +/- 0.1 nM. Methionine enkephalin was a competitive inhibitor of [3H]leucine enkephalin binding, changing the KD to 14.1 +/- 1.5 nM. In contrast, Scatchard analysis of the binding of [3H]leucine enkephalin in the absence and presence of 10, 50, and 100 nM morphine demonstrated that these concentrations of morphine decreased the number of binding sites by 23%, 32%, and 42%, respectively, with no change in the KD. In contrast, morphine at 500 nM caused a 45% decrease in the number of binding sites and an increase in the KD. On the basis of these data, the inhibitory dissociation constant (KI) of morphine was calculated to 400 +/- 17 nM. The noncompetitive inhibition by morphine of [3H]leucine enkephalin binding was shown to be rapidly reversible, ruling out pseudoirreversible binding of morphine to the enkephalin binding site as the underlying mechanism. Computer analysis of the displacement [3H]leucine enkephalin binding by various concentrations of morphine has demonstrated that an allosteric model, not a two-site model, best describes the observed data. We conclude that at low concentration morphine binds to a receptor not labeled by [3H]leucine enkephalin and by doing so allosterically induces an apparent loss of enkephalin receptors.

Allosteric Site↗
PubMed2001

Allosteric modulation of GABAA receptor by somatostatin is altered under stress in rat brainstem.

This study was conducted to investigate somatostatin modulation of GABAA receptor binding in several rat brainstem structures, located principally in the mesencephalon, after exposure to acute immobilization stress (single 1-hour session). Animals were randomly assigned to either control or stress conditions and changes in specific binding of the GABAA receptor as labelled with TBPS were assessed by in vitro quantitative autoradiography with the aid of a computer-assisted image analysis system. Exposure to immobilization stress led to a significant increase in [35S]TBPS binding site density in the SN of stressed rats compared to controls. In the other brainstem structures analysed, specific binding of [35S]TBPS remained unchanged in stressed rats. Furthermore, the results of the present in vitro study demonstrate an alteration of the modulatory effect of somatostatin on the GABAA receptor complex in the SN of stressed rats as compared to controls. This apparent alteration of allosteric effects of GABA receptor-somatostatin in the SN of stressed rats was eliminated in the presence of 1 micromolar concentration of GABA. Taken together, these data provide the first evidence of stress-induced alteration of allosteric effects of GABA-somatostatin in the rat mesencephalon. Furthermore, they also demonstrate that the tetradecapeptide somatostatin is particularly effective in modifying the [35S]TBPS binding to the GABAA receptor in this cerebral region.

Allosteric Regulation↗
PubMed1993

Postnatal development and GABA allosteric modulation of benzodiazepine receptor binding in the vitamin B-6 deficient rat brain.

We have measured the postnatal development and GABA modulation of benzodiazepine receptors in neuronal membranes from vitamin B-6 deficient and normal rats. In rats fed vitamin B-6 adequate and deficient diets there were age-dependent changes in [3H]flunitrazepam binding site affinity and in the number of binding sites. Vitamin B-6 deficiency produced a significant reduction in the potency of GABA to enhance [3H]flunitrazepam binding to cortical membranes prepared from 14 day old rats. These results suggests an uncoupling of the GABAa/benzodiazepine receptor at a developmental period when the animals are most susceptible to spontaneous seizures.

Aging↗
PubMed2005

Efficient synthesis of a GABA A alpha2,3-selective allosteric modulator via a sequential Pd-catalyzed cross-coupling approach.

A practical synthesis of 2-[3-(4-fluoro-3-pyridin-3-yl-phenyl)-imidazo[1,2-a]pyrimidin-7-yl]-propan-2-ol (1), an oral GABA(A) alpha(2/3)-selective agonist, is described. The five-step process, which afforded 1 in 40% overall yield, included imidazopyrimidine 2 and pyridine boronic acid 4 as key fragments. The synthesis is highlighted by consecutive Pd-catalyzed coupling steps to assemble the final free base 1 in high yield and regioselectivity. A novel method for Pd removal in the final step is also described.

Allosteric Regulation↗
PubMed1987

Is leucine an allosteric modulator of the lysine transporter in the intestinal basolateral membrane?

The transport of the dibasic amino acid L-lysine was investigated using basolateral membrane vesicles prepared from rat jejunal mucosal scrapings. The majority of the carrier-mediated transport was unaffected by the presence of sodium in the incubation medium, but voltage clamping of the vesicles did increase lysine uptake, indicating an associated movement of charge. Kinetic analysis of lysine influx and efflux showed the system to be symmetrical, but although the Vmax was comparable to other amino acid transport systems in this membrane, the dissociation constant for the overall reaction (KT) was an order of magnitude larger. This low affinity for lysine would explain the relatively slow rate of transport of this amino acid across the basolateral membrane. Competition experiments indicated that this system has a relatively narrow specificity carrying only lysine, arginine, ornithine, and histidine. In contrast the presence of L-leucine caused a marked stimulation of lysine efflux and influx across the vesicles. This effect was observed with leucine concentrations as low as 0.1 microM. It is concluded that although the lysine transport system in the basolateral membrane is slow in its basal state it can be rapidly turned on by the presence of L-leucine. The remarkably low concentrations required to do this suggest a possible allosteric interaction between the transporter and this neutral amino acid.

Allosteric Regulation↗
PubMed1987

Allosteric modulation of neurotoxin binding to voltage-sensitive sodium channels by Ptychodiscus brevis toxin 2.

The effects of Ptychodiscus brevis toxin 2 (PbTx-2) on the binding of neurotoxins at four different neurotoxin receptor sites on voltage-sensitive sodium channels in rat brain synaptosomes were examined. Binding of saxitoxin at neurotoxin receptor site 1 and Leiurus quinquestriatus alpha-scorpion toxin (LqTx) at neurotoxin receptor site 3 was unaffected. PbTx-2 enhanced binding of batrachotoxinin A 20-alpha-benzoate (BTX-B) to neurotoxin receptor site 2 and Centruroides suffusus suffusus beta-scorpion toxin (CsTx II) to site 4 on sodium channels. These results support the proposal that PbTx-2 and related toxins act at a new receptor site (site 5) that has not been previously analyzed in binding experiments. Half-maximal effects of PbTx-2 were observed in the range of 20-50 nM PbTx-2. The enhancement of BTX-B binding was reduced by depolarization. Saturating concentrations of PbTx-2 reduced KD values for binding of BTX-B and CsTx-II 2.9-fold and 2.6-fold, respectively. The effects of PbTx-2 and LqTx in enhancing BTX-B binding were synergistic. A model involving both preferential binding of BTX-B, PbTx-2, LqTx, and CsTx II to active states of sodium channels and allosteric interactions among the four receptor sites at which these toxins act accommodates these and previous results.

Allosteric Regulation↗
PubMed1990

Allosteric modulation of N-methyl-D-aspartate receptors.

In this review we have attempted to describe the basis for current models of the NMDA receptor, and justify the need for the various binding sites that have been proposed. The NMDA receptor is clearly a complex molecule with a number of modulatory sites, any of which may have great functional significance. From the data presented above it is apparent that the NMDA recognition site is closely coupled with the glycine site, and can also be regulated by Zn2+. The glycine site is reciprocally coupled to the NMDA site, and may also be coupled to a divalent-cation site outside the channel. However, the glycine site is insensitive to Zn2+. The Zn2+ site is probably not inside the channel to any degree, but can profoundly affect the ability of NMDA site ligands to operate the channel. However, the determination of reciprocal effects at the Zn2+ site await the development of a suitably potent and selective ligand for this site. Several lines of evidence suggest that the phencyclidine and channel-blocking Mg2+ site are located within the NMDA-operated ion channel. Glutamate, glycine, and Zn2+ alter the binding of ligands to these sites. However, this is most likely to be due to alteration of access of the ligands to their sites rather than a direct allosteric coupling. It does appear that phencyclidine site drugs and Mg2+ bind to separate sites within the channel, and that these separate sites are allosterically coupled. This complex series of interactions, many of which are mediated by endogenous agents, may allow very fine control over the expression of NMDA receptor-mediated synaptic transmission. In addition to these ligand-produced modulatory effects, there may also be covalent modification of the channel by receptor phosphorylation. Furthermore, the voltage sensitivity of some of the effects allows control of NMDA receptor-mediated signaling by alteration of the membrane potential in the postsynaptic cell, which can be achieved in a wide variety of ways. The level of sophistication possible in adjusting the responsiveness of this receptor seems entirely appropriate given its central involvement in a wide variety of fundamental neurobiological events, and underscores the deleterious pathological sequelae of the system tilting out of balance. At the same time, the wide array of possible therapeutic targets raises hopes that it may soon be possible to treat effectively some severely debilitating and currently untreatable diseases.

Allosteric Regulation↗
PubMed1987

Allosteric properties of the 5-HT2 receptor system of the rat tail artery. Ritanserin and methysergide are not competitive 5-HT2 receptor antagonists but allosteric modulators.

We present an analysis of the interactions of 5-hydroxytryptamine (5-HT) and antagonists (methysergide, ketanserin, ritanserin) with the 5-HT2 receptor system of strips of rat tail artery. The mode of action of ritanserin was also studied on strips of calf coronary arteries. 1. Ketanserin competitively antagonized 5-HT-induced effects in rat tail artery with an affinity (pKB = 9.4 nmol/l) consistent with the assumption of an interaction of 5-HT and ketanserin at 5-HT2-receptors. 2. Methysergide reduced to 50-60% the maximum response to 5-HT in rat tail artery. Concentration-effect curves for 5-HT became biphasic in the presence of methysergide with quickly and slowly developing contractions at low and high concentrations of 5-HT, respectively. 100 nmol/l ketanserin completely restored effects of 5-HT depressed by low concentrations of methysergide (less than 10 nmol/l). Higher concentrations of methysergide in the presence of 100 nmol/l ketanserin again depressed the effects of 5-HT. 3. Ritanserin resembles methysergide by causing insurmountable antagonism of 5-HT-induced contractions which can be prevented by ketanserin in both rat tail artery and calf coronary artery. These results are inconsistent with competition between ritanserin and 5-HT for the 5-HT2 receptor. 4. The findings are consistent with the assumption of an interaction of ketanserin and methysergide or ritanserin with an allosteric site near the 5-HT2-receptor. Both methysergide and ritanserin appear to antagonize the effects of 5-HT through an allosteric site which is distinct from the 5-HT2 receptor.

Allosteric Regulation↗
PubMed2001

Allosteric modulation of the GABA(A) receptor in rat hypothalamus by somatostatin is altered by stress.

1. This autoradiographic study was conducted to investigate somatostatin modulation of GABA(A) receptor binding in hypothalamic structures of immobilization-stressed rats. 2. GABA(A) receptor binding was labelled with [35S]-t- butylbicyclophosphorothionate (TBPS), which binds in or near the chloride channel. 3. Several structures of the rat hypothalamus (i.e. the peri- and paraventricular nuclei) display an increase in [35S]-TBPS binding as well as an alteration of the modulatory effect of somatostatin on the GABA(A) receptor complex under stress. Furthermore, these results demonstrate for the first time that somatostatin is particularly effective in modifying [35S]-TBPS binding to the GABA(A) receptor in rat hypothalamus.

Allosteric Regulation↗
PubMed1987

Reaction of Ascaris suum phosphofructokinase with diethylpyrocarbonate. Inactivation and desensitization to allosteric modulation.

Reaction of the phosphofructokinase from Ascaris suum with the reagent, diethylpyrocarbonate (DEPC), results in the loss of enzymatic activity. Treatment of the inactivated enzyme with hydroxylamine brings about the recovery of almost 80% of the original activity suggesting that the modified residues are histidines. Further evidence for the modification of histidines is that concomitant with the loss of activity, there is a change in A242 nm that corresponds to the derivatization of 5-6 histidines per subunit. There is no change in A278 nm during the derivatization process, thereby ruling out the modification of tyrosines by DEPC. Analyses of the first order inactivation rate constant for DEPC derivatization at different pH values resulted in the determination of a pKa of 6.4 +/- 0.1 for the group on the enzyme that reacts with DEPC. Derivatization of the enzyme with DEPC in the presence of fructose 6-phosphate (Fru-6-P) protected the enzyme against inactivation by 80%. ATP or MgATP gave no protection against DEPC inactivation. When the Fru-6-P-protected enzyme was further reacted with DEPC in the absence of Fru-6-P, a total of 2 histidines were modified per subunit, and the derivatization of one of these could be correlated with activity loss. When the phosphofructokinase that had been derivatized by DEPC in the presence of Fru-6-P was assayed, it was found that it no longer exhibited allosteric properties and appeared to be desensitized to ATP inhibition. This loss of ATP inhibition could be correlated with the modification of 2 histidines per subunit by DEPC. The first order rate constant for desensitization was determined at different pH values and a pKa value of 7.0 +/- 0.2 was obtained for the group(s) responsible for the desensitization. Regulatory studies with the desensitized enzyme revealed that the enzyme was not stimulated by AMP, NH4+, K+, phosphate, sulfate, or hexose bisphosphates. It is concluded that histidine may be involved both in the active site and the ATP inhibitory site of the ascarid phosphofructokinase.

Allosteric Regulation↗
PubMed1984

Anxiolytic cyclopyrrolone drugs allosterically modulate the binding of [35S]t-butylbicyclophosphorothionate to the benzodiazepine/gamma-aminobutyric acid-A receptor/chloride anionophore complex.

The influence of a number of anxiolytic cyclopyrrolone drugs, which include zopiclone and suriclone, on the binding of [35S]t-butylbicyclophosphorothionate (TBPS), to benzodiazepine/gamma-aminobutyric acid-A receptor/chloride anionophore complexes has been characterized in rat brain. Suriclone and its metabolites RP35,489 and RP46,166 are the most potent (IC50 approximately 3nM) inhibitors of [35S]TBPS binding thus far described, about an order of magnitude more potent than TBPS itself. The pattern of inhibition of [35S] TBPS binding by suriclone is distinctive; at approximately 10 nM there is approximately 50% inhibition of [35S]TBPS binding and inhibition "plateaus" at this level until suriclone concentrations exceed 1 microM. RP35,489 and RP46,166 display patterns of inhibition similar to suriclone. In saturation studies of [35S]TBPS binding, suriclone reduces the Bmax of [35S]TBPS-binding sites, with little or no effect on KD. Muscimol also displays a noncompetitive pattern of inhibition of [35S]TBPS binding, whereas inhibition by picrotoxinin appears competitive. [35S]TBPS dissociation is multiphasic and similar whether initiated by 10 microM TBPS or 10 microM picrotoxinin. By contrast, dissociation of [35S]TBPS is much faster (and nearly monophasic) when initiated by 10 microM TBPS/100 nM suriclone, 10 microM TBPS/1 microM muscimol, or 10 microM TBPS/1 mM pentobarbital. These results suggest that suriclone influences [35S]TBPS binding allosterically, at sites distinct from the TBPS/picrotoxinin recognition site. Inhibition of [35S]TBPS binding by suriclone varies regionally with a "plateau" at approximately 20% inhibition in the cerebellum, approximately 50% in the cerebral cortex, hippocampus and brain stem, and approximately 65% in the striatum and midbrain; by contrast, inhibition of [35S] TBPS by picrotoxinin, muscimol, and pentobarbital shows little regional variation. The inhibition of [35S]TBPS binding by suriclone is reversed by bicuculline [ED50 approximately 1 microM] in several brain regions examined. Bicuculline alone has little or no influence on [35S]TBPS binding in the cerebral cortex, hippocampus, and cerebellum, but produces a dose-dependent enhancement of [35S]TBPS binding in the striatum, midbrain, and hypothalamus. Regional differences in the effects of suriclone and bicuculline on [35S]TBPS recognition sites suggest possible heterogeneity in the coupling of cyclopyrrolone and bicuculline recognition sites to [35S]TBPS recognition sites in rat brain.

Animals↗