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The beta3-adrenoceptor agonist 4-[[(Hexylamino)carbonyl]amino]-N-[4-[2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]-phenyl]-benzenesulfonamide (L755507) and antagonist (S)-N-[4-[2-[[3-[3-(acetamidomethyl)phenoxy]-2-hydroxypropyl]amino]-ethyl]p

Abstract：

:This study identifies signaling pathways activated by the beta(2)-/beta(3)-adrenoceptor (AR) agonist zinterol, the selective beta(3)-AR agonist L755507, and the selective beta(3)-AR antagonist L748337 in CHO-K1 cells expressing human beta(3)-adrenoceptors. Zinterol and L755507 caused a robust concentration-dependent increase in cAMP accumulation (pEC(50) values of 8.5 and 12.3, respectively), whereas L748337 had low efficacy. Maximal cAMP accumulation with zinterol and L755507 was increased after pretreatment with pertussis toxin, indicating that the human beta(3)-AR couples to G(i) and to G(s). In contrast to cAMP, zinterol, L755507 and L748337 increased phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2) with very high potency (pEC(50) values of 10.9, 11.7, and 11.6). These compounds also stimulated phosphorylation of p38 mitogen-activated protein kinase (MAPK) but with much lower potency than Erk1/2 (pEC(50) values of 5.9, 5.5, and 5.7, respectively). Pertussis toxin completely blocked Erk1/2 and p38 MAPK phosphorylation in response to L748337, demonstrating a requirement for G(i/o) coupling, whereas L755507-stimulated p38 MAPK phosphorylation was not inhibited by pertussis toxin, and Erk1/2 phosphorylation was inhibited by only 30%. We found that high levels of cAMP interfered with agonist-activated p38 MAPK phosphorylation. L748337 increased extracellular acidification rate (ECAR) in the cytosensor microphysiometer with efficacy similar to zinterol and L755507, albeit with lower potency (pEC(50) value of 7.2 compared with zinterol, 8.1, and L755507, 8.6). The ECAR response to L748337 was largely via activation of p38 MAPK, demonstrated by 65% inhibition with 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-3-butyn-1-ol (RWJ67657). We conclude that the beta(3)-AR agonist L755507 couples to both G(s) and G(i) to activate adenylate cyclase and MAPK signaling, whereas the beta(3)-AR antagonist L748337 couples predominantly to G(i) to activate MAPK signaling.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Sato M,Hutchinson DS,Evans BA,Summers RJ

doi

10.1124/mol.108.046979

subject

Has Abstract

pub_date

2008-11-01 00:00:00

pages

1417-28

issue

eissn

0026-895X

issn

1521-0111

pii

mol.108.046979

journal_volume

pub_type

杂志文章

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The beta3-adrenoceptor agonist 4-[[(Hexylamino)carbonyl]amino]-N-[4-[2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]-phenyl]-benzenesulfonamide (L755507) and antagonist (S)-N-[4-[2-[[3-[3-(acetamidomethyl)phenoxy]-2-hydroxypropyl]amino]-ethyl]p