1-Alkyl-benzotriazole-5-carboxylic acids are highly selective agonists of the human orphan G-protein-coupled receptor GPR109b.
1-Substituted benzotriazole carboxylic acids have been identified as the first reported examples of selective small-molecule agonists of the human orphan G-protein-coupled receptor GPR109b (HM74), a low-affinity receptor for the HDL-raising drug niacin. No activity was observed at the highly homologous high-affinity niacin receptor GPR109a (HM74A). The high degree of selectivity was attributed to a difference in the amino acid sequence adjacent to a key arginine-ligand interaction allowing somewhat larger ligands to be tolerated by GPR109b.
Semple
Graeme
G
Skinner
Philip J
PJ
Cherrier
Martin C
MC
Webb
Peter J
PJ
Sage
Carleton R
CR
Tamura
Susan Y
SY
Chen
Ruoping
R
Richman
Jeremy G
JG
Connolly
Daniel T
DT
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008066:Lipolysis / Q000187:drug effects; D009525:Niacin / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D002264:Carboxylic Acids; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D000960:Hypolipidemic Agents; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D014230:Triazoles; D009525:Niacin; D000242:Cyclic AMP