Nicotinic acid receptor agonists differentially activate downstream effectors.
Nicotinic acid remains the most effective therapeutic agent for the treatment and prevention of atherosclerosis resulting from low high density lipoprotein cholesterol. The therapeutic actions of nicotinic acid are mediated by GPR109A, a Gi protein-coupled receptor, expressed primarily on adipocytes, Langerhans cells, and macrophage. Unfortunately, a severe, cutaneous flushing side effect limits its use and patient compliance. The mechanism of high density lipoprotein elevation is not clearly established but assumed to be influenced by an inhibition of lipolysis in the adipose. The flushing side effect appears to be mediated by the release of prostaglandin D2 from Langerhans cells in the skin. We hypothesized that the signal transduction pathways mediating the anti-lipolytic and prostaglandin D2/flushing pathways are distinct and that agonists may be identified that are capable of selectively eliciting the therapeutic, anti-lipolytic pathway while avoiding the activation of the parallel flush-inducing pathway. We have identified a number of GPR109A pyrazole agonists that are capable of fully inhibiting lipolysis in vitro and in vivo and not only fail to elicit a flushing response but can antagonize the ability of nicotinic acid to elicit a flush response in vivo. In contrast to flushing agonists, exposure of cells expressing GPR109A to the non-flushing agonists fails to induce internalization of the receptor or to activate ERK 1/2 mitogen-activated protein kinase phosphorylation.
Richman
Jeremy G
JG
Arena Pharmaceuticals, Inc., San Diego, California 92121. Electronic address: jrichman@arenapharm.com.
Kanemitsu-Parks
Martha
M
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Gaidarov
Ibragim
I
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Cameron
Jill S
JS
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Griffin
Peter
P
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Zheng
Hong
H
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Guerra
Nuvia C
NC
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Cham
Linda
L
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Maciejewski-Lenoir
Dominique
D
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Behan
Dominic P
DP
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Boatman
Doug
D
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Chen
Ruoping
R
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Skinner
Philip
P
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Ornelas
Pricilla
P
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Waters
M Gerard
MG
Division of Cardiovascular Diseases, Merck Research Laboratories, Rahway, New Jersey 07065.
Wright
Samuel D
SD
Division of Cardiovascular Diseases, Merck Research Laboratories, Rahway, New Jersey 07065.
Semple
Graeme
G
Arena Pharmaceuticals, Inc., San Diego, California 92121.
Connolly
Daniel T
DT
Arena Pharmaceuticals, Inc., San Diego, California 92121.
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008956:Models, Chemical; D018722:Nicotinic Agonists / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*
C473652:Hcar2 protein, mouse; D018722:Nicotinic Agonists; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015230:Prostaglandin D2