Regulation of human D1, D2(long), D2(short), D3and D4dopamine receptors by amiloride and amiloride analogues

Hoare, Sam R.J.; Coldwell, Martyn C.; Armstrong, Duncan; Strange, Philip G.

doi:10.1038/sj.bjp.0703370

Cited by 57 publications

(65 citation statements)

References 26 publications

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“…The potassium sparing diuretic amiloride has been shown to act as both an antagonist and an allosteric modulator for a number of GPCRs [41][42][43][44][45]. Other allosteric modulators (Fig.…”

Section: A 1 Arsmentioning

confidence: 99%

Allosteric Modulation of the Adenosine Family of Receptors

Gao¹,

Kim²,

IJzerman³

2005

MRMC

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Allosteric modulators for adenosine receptors (ARs) are of an increasing interest and may have potential therapeutic advantage over orthosteric ligands. Benzoylthiophene derivatives (including PD 81,723), 2-aminothiazolium salts, and related allosteric modulators of the A 1 AR have been studied. The benzoylthiophene derivatives were demonstrated to be selective enhancers for the A 1 AR, with little or no effect on other subtypes of ARs. Allosteric modulation of the A 2A AR has also been reported. A 3 allosteric enhancers may be predicted to be useful against ischemic conditions. We have recently characterized two classes of A 3 AR allosteric modulators: 3-(2-pyridinyl)isoquinolines (e.g. VUF5455) and 1H-imidazo-[4,5-c]quinolin-4-amines (e.g. DU124183), which selectively decreased the agonist dissociation rate at the human A 3 AR but not at A 1 and A 2A ARs. DU124183 left-shifted the agonist conc.-response curve for inhibition of forskolin-stimulated cAMP accumulation in intact cells expressing the human A 3 AR with up to 30% potentiation of the maximal efficacy. The increased potency of A 3 agonists was evident only in the presence of an A 3 antagonist, since VUF5455 and DU124183 also antagonized, i.e. displaced binding at the orthosteric site, with K i values of 1.68 and 0.82 μM, respectively. A 3 AR mutagenesis studies implicated F182 5.43 and N274 7.45 in the action of the enhancers and was interpreted using a rhodopsin-based A 3 AR molecular model, suggesting multiple binding modes. Amiloride analogues, SCH-202676 (N-(2,3-diphenyl-1,2,4-thiadiazol-5(2H)-ylidene)methanamine), and sodium ions were demonstrated to be common allosteric modulators for at least three subtypes (A 1 , A 2A , and A 3 ) of ARs.

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Section: A 1 Arsmentioning

confidence: 99%

Allosteric Modulation of the Adenosine Family of Receptors

Gao¹,

Kim²,

IJzerman³

2005

MRMC

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“…Well studied examples are D2 dopamine receptors (Hoare and Strange, 1998), muscarinic receptors (Tucek and Proska, 1995), adenosine A1 receptors (Bruns and Fergus, 1990), and ␣2-adrenergic receptors (Nunnari et al, 1987). We previously reported that aspirin and salicylic acid are allosteric inhibitors of ETA receptors (Talbodec et al, 2000).…”

mentioning

confidence: 99%

Allosteric Inhibition of Endothelin ETA Receptors by 3,5-Dibromosalicylic Acid

Blandin¹,

Vigne²,

Breittmayer³

et al. 2000

Mol Pharmacol

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Derivatives of salicylic acid (SA) and benzoic acid prevent endothelin-1 (ET-1) binding to ETA receptors. This study analyzed actions of 30 derivatives of benzoic acid and salicylic acid on 125 I-ET-1 binding to recombinant rat ETA receptors. The most active compounds were 3,5-dibromosalicylic acid (Br2SA, K i ϭ 0.5 mM) and 3,5-diiodosalicylic acid (K i ϭ 0.3 mM). They were about 50 times more potent than SA and aspirin. Br2SA inhibited equilibrium 125 I-ET-1 binding in an apparently competitive manner. It accelerated 8-fold the dissociation of 125 I-ET-1 receptor complexes and did not modify the second order rate constant of association of 125 I-ET-1 to its receptors. Br2SA also decreased the affinity of ETA receptors for receptor antagonists BQ-123 and bosentan. Br2SA accelerated dissociation of 125 I-ET-1-solubilized ETA receptor complexes and decreased the apparent molecular size of solubilized receptors. Br2SA and 3,5-diiodosalicylic acid inhibited two cellular actions of ET-1: the mobilization of intracellular Ca 2ϩ stores in isolated cells and contractions of rat aortic rings. They accelerated the relaxing action of BQ-123 and bosentan in ET-1-treated aortic rings. The results suggest the existence of an allosteric modifier site on ETA receptors that recognizes selected derivatives of SA. SA derivatives might be of therapeutic interest to relieve tight ET-1 binding and to favor actions of receptor antagonists.

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“…These modulators include SCH-202676 [21][22][23], amiloride analogues [24][25][26], agmatine [27]. The results suggested that for the P2Y 1 receptor, modes of interaction of orthosteric and allosteric binding sites might be different from that of other GPCRs.…”

Section: Discussionmentioning

confidence: 99%

2,2′-Pyridylisatogen tosylate antagonizes P2Y1 receptor signaling without affecting nucleotide binding

Gao¹,

Mamedova²,

Tchilibon³

et al. 2004

Biochemical Pharmacology

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The effect of 2,2′-pyridylisatogen tosylate (PIT) on the human P2Y 1 receptor and on other recombinant P2Y receptors has been studied. We first examined the modulation by PIT of the agonist-induced accumulation of inositol phosphates. PIT blocked 2-methylthio-ADP (2-MeSADP)-induced accumulation of inositol phosphates in 1321N1 astrocytoma cells stably expressing human P2Y 1 receptors in a non-competitive and concentration-dependent manner. The IC 50 for reduction of the maximal agonist effect was 0.14 μM. In contrast, MRS2179, a competitive P2Y 1 receptor antagonist, parallel-shifted the agonist concentration-response curve to the right. PIT also concentration-dependently blocked the P2Y 1 receptor signaling induced by the endogenous agonists, ADP and ATP. A simple structural analogue of PIT was synthesized and found to be inactive as a P2Y 1 receptor antagonist, suggesting that the nitroxyl group of PIT is a necessary structural component for P2Y 1 receptor antagonism. We next examined the possible modulation of the binding of the newly available antagonist radioligand for the P2Y 1 receptor, [ 3 H] MRS2279. It was found that PIT (0.01-10 μM) did not inhibit [ 3 H] MRS2279 binding to the human P2Y 1 receptor. PIT (10 μM) had no effect on the competition for [ 3 H] MRS2279 binding by agonists, ADP and ATP, suggesting that its antagonism of the P2Y 1 receptor may be allosteric. PIT had no significant effect on agonist activation of other P2Y receptors, including P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 and P2Y 12 receptors. Thus, PIT selectively and non-competitively blocked P2Y 1 receptor signaling without affecting nucleotide binding.

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Regulation of human D₁, D_2(long), D_2(short), D₃and D₄dopamine receptors by amiloride and amiloride analogues

Cited by 57 publications

References 26 publications

Allosteric Modulation of the Adenosine Family of Receptors

Allosteric Modulation of the Adenosine Family of Receptors

Allosteric Inhibition of Endothelin ETA Receptors by 3,5-Dibromosalicylic Acid

2,2′-Pyridylisatogen tosylate antagonizes P2Y1 receptor signaling without affecting nucleotide binding

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