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PubMed2005

Studies of the biogenic amine transporters. XI. Identification of a 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) analog that allosterically modulates the serotonin transporter.

Previous studies identified partial inhibitors of serotonin (5-HT) transporter and dopamine transporter binding. We report here on a partial inhibitor of 5-HT transporter (SERT) binding identified among a group of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine analogs (4-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-1-(2-trifluoromethyl-benzyl)-piperidine; TB-1-099). Membranes were prepared from rat brains or human embryonic kidney cells expressing the cloned human dopamine (hDAT), serotonin (hSERT), and norepinephrine (hNET) transporters. beta-(4'-(125)Iodophenyl)tropan-2beta-carboxylic acid methyl ester ([(125)I]RTI-55) binding and other assays followed published procedures. Using rat brain membranes, TB-1-099 weakly inhibited DAT binding (K(i) = 439 nM), was inactive at NET binding ([(3)H]nisoxetine), and partially inhibited SERT binding with an extrapolated plateau ("A" value) of 20%. Similarly, TB-1-099 partially inhibited [(125)I]RTI-55 binding to hSERT with an extrapolated plateau (A value) of 14%. Upon examining the effect of increasing concentrations of TB-1-099 on the apparent K(d) and B(max) of [(125)I]RTI-55 binding to hSERT, we found that TB-1-099 decreased the B(max) in a dose-dependent manner and affected the apparent K(d) in a manner well described by a sigmoid dose-response curve. TB-1-099 increased the K(d) but not to the magnitude expected for a competitive inhibitor. In rat brain synaptosomes, TB-1-099 noncompetitively inhibited [(3)H]5-HT, but not [(3)H]dopamine, uptake. Dissociation experiments indicated that TB-1-099 promoted the rapid dissociation of a small component of [(125)I]RTI-55 binding to hSERT. Association experiments demonstrated that TB-1-099 slowed [(125)I]RTI-55 binding to hSERT in a manner unlike that of the competitive inhibitor indatraline. Viewed collectively, these results support the hypothesis that TB-1-099 allosterically modulates hSERT binding and function.

Animals↗
PubMed1998

Modulating the oxygen affinity of human fetal haemoglobin with synthetic allosteric modulators.

Improving the delivery of oxygen to the tissues by decreasing the oxygen affinity of haemoglobin has been a major aim of several laboratories over recent years because this may reduce the consequences of anaemia and/or improve tissue oxygenation in cases of decreased blood perfusion. Within the same context, lowering the oxygen affinity may prove valuable in the application of native or recombinant haemoglobin solutions as a blood substitute. The shift of the oxygen equilibrium curve to the right is obtained by various modulators. Among them, the bezafibrate derivatives are considered as a most interesting group. These principles are of the utmost importance in thalassaemia and other haemoglobinopathies where the beneficial effects of the compensatory synthesis of fetal haemoglobin are diminished by the increased oxygen affinity of this pigment. In this paper we present the results of a study initiated to determine whether a potent oxygen affinity modifier, RSR-4, could satisfactorily decrease the oxygen affinity of fetal haemoglobin, thus improving tissue oxygenation. The experiments were carried out on whole blood and on purified haemoglobin solutions and showed that the effector markedly decreased the oxygen affinity of HbF (from 18.7 to 3.73 mmHg in whole blood). At the same time the cooperativity index (n50) and the oxygen saturation levels remained within normal limits under the conditions of the main experiment. These observations have important implications for the potential application of oxygen affinity modifiers in vivo.

Aniline Compounds↗
PubMed2001

Allosteric modulation of the human 5-HT(7A) receptor by lipidic amphipathic compounds.

Human 5-HT7A receptors positively modulated adenylyl cyclases via Gs subtypes of G proteins in human embryonic kidney 293 cells, and bound 5-hydroxytryptamine (HT) with high and low affinity (K(I) values of 1.5 +/- 0.3 and 93 +/- 4 nM). More than 60% of 5-HT7A receptors, however, displayed the high-affinity 5-HT binding with no sensitivity to 5'-guanylylimidodiphosphate. In this study, we found that select amphipathic agents affected the high-affinity 5-HT binding to 5-HT7A. Oleic acid at low concentrations (<15 microM), but not palmitic, stearic, and arachidonic acids, increased maximal [3H]5-HT binding without affecting its K(D) value and [3H]mesulergine (antagonist) binding. Fatty acid-free bovine serum albumin (FF-BSA), a scavenger of fatty acids and lipid metabolites, substantially reduced maximal [3H]5-HT binding (no change in K(D) value and antagonist binding) but lost its action upon treatment with inactive stearic acid. FF-BSA and oleic acid produced no appreciable effects on [3H]5-HT binding to analogous 5-HT receptors 5-HT1D and 5-HT2C. Among various lysophospholipids, lysophosphatidyl choline (50 microM) decreased maximal [3H]5-HT binding, and a similar zwitterion, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS; 0.1%), increased it (no change in K(D)). Functionally, 5-HT-induced guanosine-5'-O-(3-[35S]thio)triphosphate (GTPgamma35S) binding was enhanced by oleic acid and CHAPS, but reduced by FF-BSA and lysophosphatidyl choline; the amphipathic agents and FF-BSA did not affect dopamine-induced GTPgamma35S binding at D1, a prototypic Gs-coupled receptor. At 5-HT7A, oleic acid, FF-BSA, CHAPS, and lysophosphatidyl choline also brought about corresponding changes in the half-maximal 5-HT concentration for cAMP production, without affecting the maximal and basal levels. We propose that endogenous, amphipathic lipid metabolites may modulate 5-HT7A receptors allosterically to promote high-affinity 5-HT binding and to enable receptors to couple more efficiently to Gs subtypes of G proteins.

Allosteric Regulation↗
PubMed2005

Principles of N-methyl-D-aspartate receptor allosteric modulation.

N-methyl-D-aspartate (NMDA) receptors are glutamate-gated ion channels with complex participation in synaptic transmission, integration, and plasticity. They are highly permeable to Ca(2+), activate with characteristic kinetics, and generate currents with distinct amplitudes according to stimulation frequency. Multiple endogenous and pharmacological agents bind at distinct locations throughout the protein and modulate NMDA receptor responses with allosteric mechanisms. The NMDA receptor activation pathway consists of a series of consecutive, stepwise structural rearrangements rather than a binary, closed-open reaction. This high-resolution multistate gating reaction is used here to investigate the effects of ideal, state-specific modulators on physiologically relevant parameters of the macroscopic responses to single-pulse and high-frequency repetitive stimulation. The simulations suggest three significant aspects of NMDA receptor modulation: 1) modest, 1 kcal/mol bidirectional perturbations in receptor free energy cause up to a 50-fold change in the total charge transferred; 2) activators modulate primarily the response time course, whereas inhibitors are more effectively modulating current peak amplitude; and 3) state-specific modulators have opposite effects on charge transfer and current potentiation by high-frequency stimulation. The results imply that the magnitude of the NMDA receptor-mediated Ca(2+) influx and the receptor's ability to discriminate stimulation frequency can be controlled separately. Thus, a detailed mechanistic characterization of NMDA receptor allosteric effectors may identify function-specific modulators and provides a road map for the development of combinatorial strategies for local, transient tuning of specific receptor functions.

Allosteric Regulation↗
PubMed2006

Biochemical and pharmacological properties of an allosteric modulator site of the human P-glycoprotein (ABCB1).

The drug-transport function of the human P-glycoprotein (Pgp or ABCB1) is inhibited by a number of structurally unrelated compounds, known as modulators or reversing agents. Among them, the thioxanthene derivative flupentixol inhibits Pgp-mediated drug transport by an allosteric mechanism. Unlike most other Pgp modulators, the cis isomer of flupentixol [cis-(Z)-flupentixol] facilitates interaction of Pgp with its transport-substrate [125I]iodoarylazidoprazosin (or [125I]IAAP), yet inhibits transport. In this study, we show that the flupentixol site acts as a common site of interaction for the tricyclic ring-containing modulators thioxanthenes and phenothiazines. The allosteric stimulation of [125I]IAAP binding to Pgp occurs independent of the phosphorylation status of the transporter. Stimulation is retained in purified Pgp reconstituted into proteoliposomes, suggesting no involvement of any other cellular protein in the phenomenon. However, perturbation of the lipid environment of the reconstituted Pgp by nonionic detergent octylglucoside abolishes stimulation by cis-(Z)-flupentixol of [125I]IAAP binding. Extensive trypsin digestion of the [125I]IAAP-labeled Pgp generates a 5.5 kDa fragment with 80% of the stimulated level of labeling associated with it. Sensitivity to inhibition by transport-substrate vinblastine and competitive modulator cyclosporin A suggests that the elevated level of [125I]IAAP binding to the fragment represents a functionally relevant interaction with the substrate site of Pgp. In summary, we demonstrate that allosteric modulation by cis-(Z)-flupentixol is mediated through its interaction with Pgp at a site specific for tricyclic ring-containing Pgp modulators of thioxanthene and phenothiazine backbone, independent of other cellular components and the phosphorylation status of the protein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Use of [3H]fluorowillardiine to study properties of AMPA receptor allosteric modulators.

Compounds which modulate AMPA receptor function through allosteric mechanisms were examined for their effect on the binding of the agonist [3H]fluorowillardiine (FW). Benzamide-type positive modulators (ampakinestrade mark) under all experimental circumstances increased [3H]FW binding to native receptors in rat brain membranes. Benzothiadiazide drugs had more variable effects ranging from large reductions with cyclothiazide and JM-13 to increases produced by more recent compounds like PEPA, D1 and LY392098. These effects on binding were moderately influenced by the assay conditions, including temperature and the presence or absence of thiocyanate. Significant changes in agonist binding were also produced by other modulatory agents such as noncompetitive blockers (GYKI 53655, SYM 2206), polycationic compounds (spermine, Naspm, philanthotoxin) and polyanionic compounds (Evans Blue, suramin, PPNDS). EC50 values usually were similar to those from physiological studies, which validates using binding tests to assess drug potencies. Moreover, direction and magnitude of the binding change (Emax) provide information about which kinetic aspects are affected by a drug. For example, the magnitude of the binding increase produced by positive modulators was strongly correlated with their ability to slow response deactivation in excised patch recordings. Binding also provides a reliable method to examine whether interactions between agents are competitive. Thus, thiocyanate did not significantly influence the EC50 of cyclothiazide, suggesting distinct sites of action. Taken together, [3H]FW binding can yield important information about drug-receptor and drug-drug interactions for a wide range of modulatory agents. One potential limitation of [3H]FW is a large preference for subunits GluR1 and GluR2 (KD 4-10 nM) over GluR3 and GluR4 (160-600 nM) which implies that tests with brain membranes preferentially reveal drug effects produced at the former two subunits. Lastly, data are shown which highlight the importance of optimizing experimental conditions in filtration assays, for instance by always including thiocyanate in wash buffers.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2005

Mechanisms of allosteric modulation at GABAB receptors by CGP7930 and GS39783: effects on affinities and efficacies of orthosteric ligands with distinct intrinsic properties.

We determined the effects of the allosteric gamma-aminobutyric acid B receptor modulators CGP7930 and GS39783 on binding and function of orthosteric ligands with distinct intrinsic properties. In radioligand binding (saturation or displacement) experiments, the affinities of a number of competitive antagonists were decreased by the modulators, with no change in receptor number. The binding curves of the partial agonist CGP47656 comprised a high and a low affinity component; the affinity of the former was increased by the allosteric agents. The maximal stimulation of GTP[gamma](35)S binding via recombinant GABA(B) receptors by CGP47656 was increased 4-fold in the presence of 30 microM CGP7930 or GS39783. Two compounds known so far as "silent" competitive GABA(B) receptor antagonists, CGP35348 and 2-OH-saclofen, did not stimulate GTP[gamma](35)S binding on their own, but became low efficacy partial agonists in the presence of the two modulators. The potency of GABA to inhibit the formation of cAMP induced by a forskolin analog in a recombinant CHO cell line expressing GABA(B) receptors was increased by the modulators. CGP35348 and 2-OH-saclofen, like CGP47656, were partial agonists on their own in this assay, and the allosteric modulators increased the potency as well as the efficacy of all three compounds. With CGP52432, there was a trend towards inverse agonism in the cAMP assay. These results show that the intrinsic properties of orthosteric ligands are highly dependent on the characteristics of the assay system used and that allosteric modulators are useful tools for elucidating these properties.

Allosteric Regulation↗
PubMed2001

Effect of alpha subunit on allosteric modulation of ion channel function in stably expressed human recombinant gamma-aminobutyric acid(A) receptors determined using (36)Cl ion flux.

Inhibitory gamma-aminobutyric acid (GABA)(A) receptors are subject to modulation at a variety of allosteric sites, with pharmacology dependent on receptor subunit combination. The influence of different alpha subunits in combination with beta3gamma2s was examined in stably expressed human recombinant GABA(A) receptors by measuring (36)Cl influx through the ion channel pore. Muscimol and GABA exhibited similar maximal efficacy at each receptor subtype, although muscimol was more potent, with responses blocked by picrotoxin and bicuculline. Receptors containing the alpha3 subunit exhibited slightly lower potency. The comparative pharmacology of a range of benzodiazepine site ligands was examined, revealing a range of intrinsic efficacies at different receptor subtypes. Of the diazepam-sensitive GABA(A) receptors (alpha1, alpha2, alpha3, alpha5), alpha5 showed the most divergence, being discriminated by zolpidem in terms of very low affinity, and CL218,872 and CGS9895 with different efficacies. Benzodiazepine potentiation at alpha3beta3gamma2s with nonselective agonist chlordiazepoxide was greater than at alpha1, alpha2, or alpha5 (P < 0.001). The presence of an alpha4 subunit conferred a unique pharmacological profile. The partial agonist bretazenil was the most efficacious benzodiazepine, despite lower alpha4 affinity, and FG8205 displayed similar efficacy. Most striking were the lack of affinity/efficacy for classical benzodiazepines and the relatively high efficacy of Ro15-1788 (53 +/- 12%), CGS8216 (56 +/- 6%), CGS9895 (65 +/- 6%), and the weak partial inverse agonist Ro15-4513 (87 +/- 5%). Each receptor subtype was modulated by pentobarbital, loreclezole, and 5alpha-pregnan-3alpha-ol-20-one, but the type of alpha subunit influenced the level of potentiation. The maximal pentobarbital response was significantly greater at alpha4beta3gamma2s (226 +/- 10% increase in the EC(20) response to GABA) than any other modulator. The rank order of potentiation for pregnanolone was alpha5 > alpha2 > alpha3 = alpha4 > alpha1, for loreclezole alpha1 = alpha2 = alpha3 > alpha5 > alpha4, and for pentobarbital alpha4 = alpha5 = alpha2 > alpha1 = alpha3.

Allosteric Regulation↗
PubMed2001

Interactions between allosteric modulators and 4-DAMP and other antagonists at muscarinic receptors: potential significance of the distance between the N and carboxyl C atoms in the molecules of antagonists.

Allosteric enhancement of the affinity of muscarinic receptors for their ligands offers a new way to influence cholinergic neurotransmission. The structure of the allosteric binding domain(s) and the features of agonists, antagonists and modulators which determine the occurrence of either positive or negative cooperativity require clarification. We tested interactions between allosteric modulators alcuronium, strychnine and brucine and eight antagonists at muscarinic receptors expressed in CHO cells. In experiments with unlabeled antagonists, all three modulators enhanced the affinity for 4-diphenylacetoxy-N-dimethylpiperidinium (4-DAMP) at the M2 receptors, and strychnine did so also at the M4 receptors. Positive interactions were also observed between alcuronium and L-hyoscyamine (M2) and scopolamine (M2), between strychnine and butylscopolamine (M4), L-hyoscyamine (M2 and M4) and scopolamine (M4), and between brucine and scopolamine (M2). Positive effects of alcuronium, strychnine and brucine on the affinity of the M2 receptors for 4-DAMP have been confirmed by direct measurements of the binding of [3H]-4-DAMP. A comparison of molecular models of several antagonists which are esters revealed that antagonists in which the distance between the N and the carboxyl C atoms corresponds to five chemical bonds are more likely to display positive cooperativity with alcuronium at the M2 receptors than the antagonists in which the N-carboxyl C distance corresponds to four chemical bonds.

Alcuronium↗
PubMed1994

Search for the pharmacophore of bispyridinium-type allosteric modulators of muscarinic receptors.

The bis(dichlorobenzyl) ether of the bispyridinium oxime TMB 4 stabilizes antagonist binding to M2-cholinoceptors which is indicative of an allosteric action. More than 10 derivatives of the lead compound were synthesized to investigate structure-activity relationships. The allosteric potency of the compounds was indicated by the concentrations which retarded the rate of dissociation of [3H]N-methylscopolamine from porcine cardiac cholinoceptors by a factor of 2 (EC50). Compared with TMB 4, the bis(dichlorobenzyl) derivative 4a displayed a more than 200-fold higher potency (EC50 = 4.7 microM). One of the dichlorobenzyl groups could be replaced by a methyl group without loss of activity (EC50 = 4.5 microM). Further shortening of this end of the molecule was accompanied by a moderate decline in potency to a minimum of EC50 = 26 microM. The second quaternary nitrogen was not a prerequisite for an allosteric activity. It is concluded that one half of the lead compound is pivotal for an interaction with the allosteric site of the M2-cholinoceptor, whereas the opposite end of the molecule modulates the allosteric activity.

Allosteric Regulation↗
PubMed1999

Allosteric modulators of the AMPA receptor: novel 6-substituted dihydrophthalazines.

Novel analogs of the allosteric AMPA receptor modulator SYM 2206 have been prepared. Structure/activity correlations of these novel analogs and other dihydrophthalazines (DHPs) reveal the important contribution of the heteroatom-based aryl substituents in this class of noncompetitive inhibitors. One of the analogs (6, SYM 2189) is equipotent with the early series, but with reduced sedation.

Allosteric Regulation↗
PubMed2004

Repeated dosing with oral allosteric modulator of adenosine A1 receptor produces tolerance in rats with neuropathic pain.

BACKGROUND: The positive allosteric adenosine receptor modulator, T62 (2-amino-3-(4-chlorobenzoyl)-5,6,7,8-tetrahydrobenzothiophene), has been shown to reduce mechanical allodynia in a rat model of neuropathic pain. However, whether chronic oral T62 retains efficacy in this pain model has not been examined. Therefore, the authors studied antiallodynic effects of chronic oral T62 in spinal nerved-ligated rats, as well as motor and sedative behavioral effects. METHODS: Oral T62, 100 mg/kg, or oral oil was applied daily to spinal nerve-ligated rats for 4 weeks, with rat weights examined daily. Sedation, placing and ambulation scores, and withdrawal threshold were observed for 3 h daily for the first 2 weeks and then once a week. At the end of observation, the animals were killed, and the spinal tissues were collected for radioligand binding. In addition, withdrawal thresholds were also observed in rats with 5 days of treatment with 50 mg/kg oral T62. Furthermore, the effects of intrathecal adenosine on rats with oral T62 or oil treatment were compared. RESULTS: Chronic oral T62, at 100 mg/kg, initially returned the withdrawal threshold to mechanical testing to preinjury levels, with minor or no sedative or motor effects. Tolerance was observed, with a 60% loss of most possible effects in antiallodynia within 5 days of daily administration. Similarly, tolerance also occurred with chronic oral T62 at 50 mg/kg but did not alter the effect of intrathecal adenosine. Furthermore, 4 weeks of exposure to 100 mg/kg T62 resulted in a small reduction in spinal cord A1 receptor number. CONCLUSION: The results imply that chronically administered A1 adenosine modulators lose efficacy over time, partly as a result of receptor down-regulation.

Adenosine↗
PubMed2000

Bisquaternary caracurine V derivatives as allosteric modulators of ligand binding to M2 acetylcholine receptors.

The allosteric effect on muscarinic acetylcholine M2 receptors of 11 bisquaternary salts of the Strychnos alkaloid caracurine V was determined. The effect was indicated by the concentration which retarded the rate of dissociation of the antagonist [3H]-N-methylscopolamine from porcine cardiac cholinoceptors by a factor of 2 (EC50). The most potent compounds carry allyl and propargyl substituents, respectively. Introduction of more bulky substituents (e.g., benzyl groups) resulted in a considerably reduced allosteric potency. The wide range of EC50 values (3 nM for R = allyl. 1750 nM for R = 2-naphthyl) suggests a sterically restricted binding pocket. Molecular modeling studies indicated that the caracurine V ring system satisfies the pharmacophore model for the allosteric interaction.

Alkaloids↗
PubMed1999

Allosteric modulation of the adenosine A(1) receptor. Synthesis and biological evaluation of novel 2-amino-3-benzoylthiophenes as allosteric enhancers of agonist binding.

Novel allosteric enhancers of agonist binding to the rat adenosine A(1) receptor are described. The lead compound for the new series was PD 81,723 ((2-amino-4, 5-dimethyl-3-thienyl)[3-(trifluoromethyl)phenyl]methanone), a compound previously reported by Bruns and co-workers (Mol. Pharmacol. 1990, 38, 950-958). The 4,5-dimethyl group and the benzoyl moiety were targets for further modifications, leading to series of 4, 5-dialkyl (12a-g), of tetrahydrobenzo (12h-u), and of tetrahydropyridine (13a-g) derivatives. A number of compounds, in particular 12b, 12e, 12j, 12n, and 12u, proved superior to PD 81,723. Their EC(50) values for enhancing the binding of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine to the receptor were lower, and/or their antagonistic activity on the adenosine A(1) receptor was shown to be diminished.

Adenosine↗
PubMed1994

Residue lysine-34 in GroES modulates allosteric transitions in GroEL.

The conserved residue Lys-34 in GroES was replaced by alanine and glutamic acid using site-directed mutagenesis. This residue is near the carboxy terminus of the mobile loop in GroES (residues 17-32) which becomes immobilized upon formation of the GroEL/GroES complex [Landry et al. (1993) Nature 364, 255-258]. Both charge neutralization (Lys-34-->Ala) and charge reversal (Lys-34-->Glu) at this position have little effect on the binding constant of GroES to GroEL, but they increase the enhancement by GroES of cooperativity in ATP hydrolysis by GroEL. This is reflected by a change in the Hill coefficient (at 10 mM K+) from 4.10 (+/- 0.22) in the presence of wild-type GroES to 5.17 (+/- 0.24) and 4.46 (+/- 0.14) in the presence of the GroES mutants Lys-34-->Ala and Lys-34-->Glu, respectively. The results are interpreted using the Monod-Wyman-Changeux (MWC) model for cooperativity [Monod et al. (1965) J. Mol. Biol. 12, 88-118]. They suggest that Lys-34 in GroES modulates the allosteric transition in GroEL by stabilizing a relaxed (R)-like state.

Adenosine Triphosphatases↗
PubMed2006

Allosteric modulation of [3H]EBOB binding to GABAA receptors by diflunisal analogues.

Allosteric modulatory effects of 12 biphenyl derivatives of diflunisal and two fenamates were studied on A-type receptors of GABA (GABAAR) via [3H]4'-ethynylbicycloorthobenzoate (EBOB) binding to synaptic membrane preparations of rat forebrain. A simplified ternary allosteric model was used to determine binding affinities of the compounds and the extents of cooperativity with GABA. Structure activity analysis revealed that 4-hydroxy substituents of the biphenyls contribute to their micromolar binding affinities more than 3-carboxyl groups. Electron-withdrawing fluorinated substituents, especially in ortho position, were also advantageous. These factors also strongly enhanced the cooperativity with GABA binding. The correlation between displacing potency of the allosteric agents and cooperativity with GABA suggests that these processes are associated with common mechanisms. The pharmacological relevance of these interactions is discussed. These data help to differentiate the structural requirements of these agents to act on GABAergic neurotransmission versus nonsteroidal anti-inflammatory effects.

Affinity Labels↗
PubMed1993

Allosteric modulations of the nicotinic acetylcholine receptor.

The nicotinic acetylcholine receptor behaves as an allosteric protein with multiple, interconvertible conformations: a resting state, an open channel state and several desensitized states. A variety of pharmacological agents and physiological ligands regulate the transitions between these states when they bind to sites topographically distinct from the acetylcholine binding site. The physiological significance of this type of regulation is discussed and its potential role in the modulation of synaptic efficacy suggested.

Acetylcholine↗
PubMed2000

Allosteric modulation of A(2A) adenosine receptors by amiloride analogues and sodium ions.

Allosteric regulation of rat A(2A) adenosine receptors by amiloride, amiloride analogues, and sodium ions was studied by investigating their ability to influence the dissociation of [(3)H]4-2-[7-amino-2-(2-furyl)-1,2,4-triazolo[1,5-a][1,3, 5]triazin-5-yl-amino]ethylphenol ([(3)H]ZM241385) from receptors in rat striatal membranes. Both amiloride and its analogues accelerated the dissociation, the analogues being more potent than amiloride itself. In contrast, sodium ions decreased the rate of [(3)H]ZM241385 dissociation in a concentration-dependent manner, and this rate was not influenced by guanosine triphosphate, N-ethylmaleimide, suramin, or the selective A(2A) adenosine receptor antagonist, 5-amino-2-(2-furyl)-7(2-phenylethyl)pyrazolo[4,3-e]-1,2, 4-triazolo[1,5-c]pyrimidine (SCH58261). The effect of competition between the amiloride analogue 5-(N,N-hexamethylene)amiloride (HMA) and sodium ions on [(3)H]ZM241385 dissociation was also explored. The addition of sodium ions resulted in a concentration-dependent rightward shift of the HMA response curve. The slopes of the HMA concentration-response curves in the presence and absence of sodium ions were not significantly different, which suggests that sodium ions and amiloride analogues act at a common allosteric site on the A(2A) adenosine receptor. There was a lack of correlation between the displacement of ligand binding and the allosteric potencies of the amiloride analogues.

Allosteric Regulation↗