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Stereoselectivity at the B2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of B2-agonists

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Author: Izeboud, C.A. · Vermeulen, R.M. · Zwart, A. · Vos, H.P. · Miert, A.S.J.P.A.M. van · Witkamp, R.F.
Source:Naunyn-Schmiedeberg's Archives of Pharmacology, 362, 184-189
Identifier: 56797
doi: doi:10.1007/s002100000281
Keywords: 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


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.