Allosteric enhancer PD 81,723 acts by novel mechanism to potentiate cardiac actions of adenosine.

Kollias-Baker, Cynthia; Ruble, Jackie; Dennis, Donn M.; Bruns, Robert F.; Linden, Joel; Belardinelli, Luiz

doi:10.1161/01.res.75.6.961

Cited by 46 publications

(34 citation statements)

References 22 publications

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“…agonists. Thus, in equilibrium binding assays employing agonist radioligands, both PD81,723 (Kollias-Baker et al, 1994;Bhattacharya and Linden, 1995) and ATL525 increase the fraction of receptors found in the high-affinity (G proteincoupled) state, but have little or no effect on the radioligand K D . These findings suggest the enhancers stabilize the conformational state of receptors that bind agonists with high affinity.…”

Section: Discussionmentioning

confidence: 99%

Allosteric Enhancers of A₁Adenosine Receptors Increase Receptor-G Protein Coupling and Counteract Guanine Nucleotide Effects on Agonist Binding

Figler¹,

Olsson²,

Linden³

2003

Mol Pharmacol

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Endogenous ligands of G protein-coupled receptors bind to orthosteric sites that are topologically distinct from allosteric sites. Certain aminothiophenes such as (2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluromethyl)-phenyl]-methanone (PD81,723) and 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-biphenyl-4-yl-methanone (ATL525) are positive allosteric regulators, or enhancers, of the human A 1 adenosine receptor (A 1 AR). In equilibrium binding assays, 125

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Section: Discussionmentioning

confidence: 99%

Allosteric Enhancers of A₁Adenosine Receptors Increase Receptor-G Protein Coupling and Counteract Guanine Nucleotide Effects on Agonist Binding

Figler¹,

Olsson²,

Linden³

2003

Mol Pharmacol

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“…5) with the dissociation rate constant of [ (Hollmann and Heinemann, 1994), strychnine-sensitive glycine receptors (Mascia et al, 1996), P2X purinoceptors (Pintor et al, 1996), and nicotinic cholinergic receptors (Schrattenholz et al, 1996)]. Among G protein-coupled receptors, only the adenosine A 1 receptor is known to have an allosteric site that supports positive cooperativity with the endogenous ligand (Kollias-Baker et al, 1994). The current finding of positive cooperativity with the endogenous ligand at muscarinic receptors raises the possibility that other G protein-coupled receptors, perhaps including ␣ 2 -adrenergic, dopamine D 2 , and 5-hydroxytryptamine 1B/1D receptors (Nunnari et al, 1987;Hoare and Strange, 1996;Massot et al, 1996), also may have such allosteric sites.…”

Section: Discussionmentioning

confidence: 99%

Subtype-Selective Positive Cooperative Interactions between Brucine Analogues and Acetylcholine at Muscarinic Receptors: Radioligand Binding Studies

Lazareno

Gharagozloo²,

Kuonen³

et al. 1998

Mol Pharmacol

105

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We studied the interactions of strychnine, brucine, and three of the N-substituted analogues of brucine with [3 H]N-methylscopolamine (NMS) and unlabeled acetylcholine at m1-m5 muscarinic receptors using equilibrium and nonequilibrium radioligand binding studies. The results were consistent with a ternary allosteric model in which both the primary and allosteric ligands bind simultaneously to the receptor and modify the affinities of each other. The compounds had K d values in the submillimolar range, inhibited [ 3 H]NMS dissociation, and showed various patterns of positive, neutral, and negative cooperativity with [ 3 H]NMS and acetylcholine, but there was no predictive relationship between the effects. Acetylcholine affinity was increased ϳ2-fold by brucine at m1 receptors, ϳ3-fold by Nchloromethyl brucine at m3 receptors, and ϳ1.5-fold by brucine-N-oxide at m4 receptors. The existence of neutral cooperativity, in which the compound bound to the receptor but did not modify the affinity of acetylcholine, provides the opportunity for a novel form of drug selectivity that we refer to as absolute subtype selectivity: an agent showing positive or negative cooperativity with the endogenous ligand at one receptor subtype and neutral cooperativity at the other subtypes would exert functional effects at only the one subtype, regardless of the concentration of agent or its affinities for the subtypes. Our results demonstrate the potential for developing allosteric enhancers of acetylcholine affinity at individual subtypes of muscarinic receptor and suggest that minor modification of a compound showing positive, neutral, or low negative cooperativity with acetylcholine may yield compounds with various patterns of cooperativity across the receptor subtypes.

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“…The cardiovascular effects of PD 81,723 have been studied extensively [24][25][26][27][28][29][30]. The slowing effects of PD 81,723 on nodal conduction mimicked those of adenosine acting at the A 1 AR.…”

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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Allosteric enhancer PD 81,723 acts by novel mechanism to potentiate cardiac actions of adenosine.

Cited by 46 publications

References 22 publications

Allosteric Enhancers of A₁Adenosine Receptors Increase Receptor-G Protein Coupling and Counteract Guanine Nucleotide Effects on Agonist Binding

Allosteric Enhancers of A₁Adenosine Receptors Increase Receptor-G Protein Coupling and Counteract Guanine Nucleotide Effects on Agonist Binding

Subtype-Selective Positive Cooperative Interactions between Brucine Analogues and Acetylcholine at Muscarinic Receptors: Radioligand Binding Studies

Allosteric Modulation of the Adenosine Family of Receptors

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Allosteric enhancer PD 81,723 acts by novel mechanism to potentiate cardiac actions of adenosine.

Cited by 46 publications

References 22 publications

Allosteric Enhancers of A1Adenosine Receptors Increase Receptor-G Protein Coupling and Counteract Guanine Nucleotide Effects on Agonist Binding

Allosteric Enhancers of A1Adenosine Receptors Increase Receptor-G Protein Coupling and Counteract Guanine Nucleotide Effects on Agonist Binding

Subtype-Selective Positive Cooperative Interactions between Brucine Analogues and Acetylcholine at Muscarinic Receptors: Radioligand Binding Studies

Allosteric Modulation of the Adenosine Family of Receptors

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Allosteric Enhancers of A₁Adenosine Receptors Increase Receptor-G Protein Coupling and Counteract Guanine Nucleotide Effects on Agonist Binding

Allosteric Enhancers of A₁Adenosine Receptors Increase Receptor-G Protein Coupling and Counteract Guanine Nucleotide Effects on Agonist Binding