trans-Activation and repression properties of the novel nonsteroid glucocorticoid receptor ligand 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(1-methylcyclohexen-3-y1)-1H-[1]benzopyrano[3,4-f]quinoline (A276575) and its four stereoisomers.
Glucocorticoids are potent anti-inflammatory and immunosuppressant agents. However, they also produce serious side effects that limit their usage. It has been proposed that anti-inflammatory properties of glucocorticoids are caused mostly by repression of activator protein 1- and nuclear factor kappabeta-stimulated synthesis of inflammatory mediators, whereas most of their adverse effects are associated with trans-activation of genes involved with metabolic processes. Our laboratories have sought to discover novel glucocorticoid receptor (GR) ligands that have high repression but low trans-activation activities. We describe here cellular properties of 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(1-methylcyclohexen-3-y1)-1H-[1]benzopyrano[3,4-f]quinoline (A276575) and its four enantiomers. Similar to dexamethasone, A276575 exhibited high affinity for GR and potently repressed interleukin (IL) 1beta-stimulated IL-6 production in human skin fibroblasts, prostaglandin (PG) E(2) production in A549 human lung epithelial cells, and concanavalin A-induced monocyte proliferation. In contrast to dexamethasone, A276575 caused smaller induction of aromatase activity in human skin fibroblasts and antagonized dexamethasone-induced activation of an mouse mammary tumor virus-glucocorticoid-response element (GRE) reporter gene construct. Among the four enantiomers of A276575, the two (-)-enantiomers showed 10- to 30-fold higher affinities for GR than their respective (+)-enantiomers. Both (-)-Syn and (-)-Anti enantiomers of A276575 were potent inhibitors of IL-1beta-stimulated PGE2 production in A549 lung epithelial cells; unexpectedly, however, only the (-)-Anti enantiomer inhibited regulated on T-cell activation, normal T-cell expressed and secreted (RANTES) production in A549 cells. In summary, A276575 is a novel, nonsteroidal GR ligand that possesses high repression activities against inflammatory mediator production but has lower GRE trans-activation activities than traditional steroids. Differential repression of RANTES and PGE2 production in a cell by the two (-)-enantiomers of A276575 illustrates the complexity of repression by GR.
Immunoscience Department, Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064-6117, USA. chun.lin@abbott.com
Chun Wel
CW
Lin
Masaki
M
Nakane
Mike
M
Stashko
Doug
D
Falls
Jane
J
Kuk
Loan
L
Miller
Ruth
R
Huang
Curtis
C
Tyree
Jeffrey N
JN
Miner
John
J
Rosen
Philip R
PR
Kym
Mike J
MJ
Coghlan
George
G
Carter
Ben C
BC
Lane
D001141:Aromatase / Q000378:metabolism; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D018946:Chemokine CCL5 / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004347:Drug Interactions; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D020868:Gene Silencing / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011980:Receptors, Progesterone / Q000819:agonists / Q000037:antagonists & inhibitors; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D013237:Stereoisomerism; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection
C461485:2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(1-methylcyclohexen-3-y1)-1H-(1)benzopyrano(3,4-f)quinoline; D001578:Benzopyrans; D018946:Chemokine CCL5; D007375:Interleukin-1; D015850:Interleukin-6; D011804:Quinolines; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D003208:Concanavalin A; D001141:Aromatase; D015232:Dinoprostone