Kinetic and functional properties of [3H]ZM241385, a high affinity antagonist for adenosine A2A receptors

Uustare, Ain; Vonk, Argo; Terasmaa, Anton; Fuxé, Kjell; Rinken, Ago

doi:10.1016/j.lfs.2004.10.027

Cited by 36 publications

(26 citation statements)

References 38 publications

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“…That was also the case in our system, where 5-HT caused concentration dependent binding of [ 35 [26,27], but considerably lower than it could be expected from the radioligand binding (Table 2). Here it would be assumed that the discrepancies found between functional properties of the ligands and their abilities to compete with the radioligand binding can be caused by the kinetics of conformational isomerizations as it has been found for adenosine A 2A receptors [28] or by cooperative regulation of interacting binding sites as it has been found for melanocortin receptors [29] or by peculiarities of signal transduction system [30].…”

Section: Resultsmentioning

confidence: 99%

Characteristics of Binding of [3H]WAY100635 to Rat Hippocampal Membranes

Parkel

Rinken

2006

Neurochem Res

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Kinetic analysis of binding of [(3)H][N-[2-[4-(2-[O-methyl-(3)H]methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane carboxamide ([(3)H]WAY100635) to 5-HT(1A) receptors in rat hippocampal membranes has revealed complex regulation mechanism for this radioligand. Saturation binding experiments revealed that [(3)H]WAY100635 binds to a single class of receptors with very high apparent affinity (K (D) = 87 +/- 4 pM, B (max) = 15.1 +/- 0.2 fmol/mg protein). The binding was almost irreversible, as the dissociation rate constant obtained k (off) = (7.8 +/- 1.1) x 10(-3) min(-1), means that equilibrium with this radioligand cannot be achieved before 7.5 h incubation at 25 degrees C. Systematic association kinetic studies of [(3)H]WAY100635 binding revealed sharp reaction acceleration at higher radioligand concentration, proposing mechanism of positive cooperativity. The affinities of antagonists determined from competition with [(3)H]WAY100635 did not coincide with their abilities to inhibit 5-HT-dependent activation of [(35)S]GTPgammaS binding probably due to the ligand's kinetic peculiarities. Thus, [(3)H]WAY100635 appears to be an excellent tool for determining receptor binding sites, but its applicability in equilibrium studies is strongly limited.

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Section: Resultsmentioning

confidence: 99%

Characteristics of Binding of [3H]WAY100635 to Rat Hippocampal Membranes

Parkel

Rinken

2006

Neurochem Res

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“…35 The four adenosine receptor sub-types (A 1 A 2A R antagonists have generally been derived directly from xanthine, or contain heterocyclic scaffolds which are closely related to other purines such as adenine. 36,38 Typical examples include the purine-like derivative ZM241385, a potent and selective A 2A R inverse agonist which has been used widely as a research tool, 39,40 and the xanthine derivative, caffeine, a weak, non-selective adenosine receptor antagonist.…”

Section: Adenosine a 2a Receptor And Parkinson's Diseasementioning

confidence: 99%

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A_2A receptor

Andrews

Tehan

2013

Med. Chem. Commun.

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Significant progress has been made with stabilising G protein-coupled receptors (GPCRs) in recent years, and this has enabled the structures of several members of this important target class to be solved by X-ray crystallography. High resolution structural data is improving our understanding of GPCR activation and function, and is beginning to impact the drug discovery community. StaR ® proteins are GPCRs which have been minimally-engineered to impart thermostability. StaRs ® are stable in detergent micelles and are suitable reagents for use with X-ray crystallography, biophysical screening techniques and fragment screening.This article reviews the role that StaRs ® can play in the identification and optimisation of novel ligands for GPCRs by examining a specific case in which a preclinical candidate for the treatment of Parkinson's disease was developed. Compound 13 was identified following the virtual screening of experimentally-enabled homology models of adenosine A 2A receptor (A 2A R) and was subsequently optimised using the structural insight provided by X-ray crystallography and Biophysical Mapping of closely-related molecules. Compound 19 is an exemplar from this chemical series which displays low molecular weight and high oral bioavailability; it has a good pharmacokinetic profile and is highly efficacious in preclinical models of Parkinson's disease.

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“…The kinetic analysis of the ligand interaction with adenosine A 2A receptors showed that the reaction had at least two subsequent steps. The first step corresponds to a fast equilibrium, while the second to a slow process of conformational isomerization [13]. Since ARs couple to G proteins, they exist in two affinity states with respect to the binding of agonists, high affinity (coupled) and low affinity Although A 1 adenosine receptors are most abundant in limbic and neocortical regions, they are also abundant in the basal ganglia and cerebellum and are also present in most nuclei in the diencephalons and brain stem.…”

Section: A 1 and A 2a Adenosine Receptors Distribution And Signalingmentioning

confidence: 99%

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

Yuzlenko

Kieć‐Kononowicz

2006

CMC

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This review summarizes the current tendencies observed in the past 5 years in the development of A(1) and A(2A) adenosine receptor antagonists performed in various academia and industry. A(1) and A(2A) AR antagonists are as well xanthines as heteroaromatic derivatives and are most commonly 6:5 fused heteroatomic compounds. Among xanthine-based compounds, some common features could be pointed out. The recent A(1) AR ligands which show good biological profile, possess long alkyl chains in position 1 and 3 as well as bulky C(8)-substituent, while A(2A) AR antagonists with a high A(2A) AR affinity are C(8)-styryl substituted with N(1)-alkyl/alkynyl moiety or fused tricyclic xanthines possessing heteroatom(s) in the third cycle. The research in the field of heteroaromatic A(1) and A(2A) ARs antagonists impressively has a wide range. Ligands are as well non-fused monocyclic substituted compounds as fused bi- and tricyclic derivatives with the nitrogen, oxygen and sulfur heteroatoms. Most often, adenosine A(1) receptor non-xanthine antagonists are adenine-based, having substituted amino group and variable nitrogen atoms positions in the molecules. A(2A) AR ligands show good affinity when furanyl function, which is crucial for binding, is present in the fused bicyclic and tricyclic analogs. Moreover, tricyclic nitrogen containing antagonists in order to be active, frequently possess long-alkylphenyl moiety.

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Kinetic and functional properties of [3H]ZM241385, a high affinity antagonist for adenosine A2A receptors

Cited by 36 publications

References 38 publications

Characteristics of Binding of [3H]WAY100635 to Rat Hippocampal Membranes

Characteristics of Binding of [3H]WAY100635 to Rat Hippocampal Membranes

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A_2A receptor

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

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Kinetic and functional properties of [3H]ZM241385, a high affinity antagonist for adenosine A2A receptors

Cited by 36 publications

References 38 publications

Characteristics of Binding of [3H]WAY100635 to Rat Hippocampal Membranes

Characteristics of Binding of [3H]WAY100635 to Rat Hippocampal Membranes

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

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Product

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Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A_2A receptor