Title
Stereoselectivity at the B2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of B2-agonists
Author
Izeboud, C.A.
Vermeulen, R.M.
Zwart, A.
Vos, H.P.
van Miert, A.S.J.P.A.M.
Witkamp, R.F.
Publication year
2000
Abstract
Previous research has shown that β-adrenoceptor (β-AR) agonists have potent anti-inflammatory capabilities, e.g. represented by suppression of release of the proinflammatory cytokines. Aim of this research was to determine whether the effects of β-agonists on LPS-induced TNFα and IL-10 release are influenced by their different stereochemistry. In addition, the role of the β-AR subtypes was studied. The effect of two stereoisomers of the selective β2-AR agonist TA2005 [(R,R)- and (S,S)-] on the LPS-induced TNFα and IL-10 release by U937 macrophages was compared. The (R,R)-stereoisomer was 277 times more potent in inhibiting the TNFα release than the (S,S)-form. The (R,R)-stereoisomer also appeared to be more potent in increasing the IL-10 release. In radioligand binding studies the affinity of (R,R)-TA2005 for the β-adrenoceptor was 755 times higher than the (S,S)-TA2005 stereoisomer. In addition, the elevation of intracellular cAMP in U937 cells appeared to be stereoselective: (R,R)-TA2005 was more potent in elevating intracellular cAMP. The effect of both stereoisomers on the LPS-induced TNFα release could almost completely be antagonized by preincubation with the selective β2-AR-antagonist ICI-118551. Further evidence that the effect of the β-agonists is mediated via the β2-adrenoceptor subtype exclusively was acquired by incubation of U937 cells with selective β1- and β3-agonists. None of these receptor subtype agonists showed significant suppressive effect on TNFα release. This study provides additional proof that the anti-inflammatory effects of β2-agonists are mediated via the β2-adrenoceptor and indicates that these effects are highly dependent on the stereoselectivity of the ligand.
Subject
β-Adrenoceptor
Stereoselectivity
3 isopropylamino 1 (7 methyl 4 indanyloxy) 2 butanol
4 (3 tert butylamino 2 hydroxypropoxy) 2 benzimidazolone
Aprotinin
Benzylsulfonyl fluoride
Beta 2 adrenergic receptor
Beta 2 adrenergic receptor blocking agent
Beta 2 adrenergic receptor stimulating agent
Carmoterol
cyclic AMP
Interleukin 10
Lipopolysaccharide
Tumor necrosis factor alpha
Xamoterol
Beta adrenergic receptor stimulating agent
Nonsteroid antiinflammatory agent
Antiinflammatory activity
Stereochemistry
Cell culture
Cell membrane
Drug antagonism
Metabolism
Radioassay
Signal transduction
Stereoisomerism
Adrenergic beta-Agonists
Anti-Inflammatory Agents, Non-Steroidal
Cell Membrane
Cells, Cultured
Cyclic AMP
Humans
Interleukin-10
Lipopolysaccharides
Macrophages
Radioligand Assay
Receptors, Adrenergic, beta-2
Signal Transduction
Stereoisomerism
Tumor Necrosis Factor-alpha
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DOI
https://doi.org/10.1007/s002100000281
TNO identifier
56797
Source
Naunyn-Schmiedeberg's Archives of Pharmacology, 362, 184-189
Document type
article