title: Structure-activity relationships of trans-substituted-propenoic acid derivatives on the nicotinic acid receptor HCA2 (GPR109A).
abstract: Nicotinic acid (niacin) has been used for decades as an antidyslipidemic drug in man. Its main target is the hydroxy-carboxylic acid receptor HCA2 (GPR109A), a G protein-coupled receptor. Other acids and esters such as methyl fumarate also interact with the receptor, which constituted the basis for the current study. We synthesized a novel series of substituted propenoic acids, such as fumaric acid esters, fumaric acid amides and cinnamic acid derivatives, and determined their affinities for the HCA2 receptor. We observed a rather restricted binding pocket on the receptor with trans-cinnamic acid being the largest planar ligand in our series with appreciable affinity for the receptor. Molecular modeling and analysis of the structure-activity relationships in the series suggest a planar trans-propenoic acid pharmacophore with a maximum length of 8 Å and out-of-plane orientation of the larger substituents.
authors.affiliation: Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: J P D
authors.initials: JP
authors.lastname: van Veldhoven
authors.forename: C C
authors.initials: CC
authors.lastname: Blad
authors.forename: C M
authors.initials: CM
authors.lastname: Artsen
authors.forename: C
authors.initials: C
authors.lastname: Klopman
authors.forename: D R
authors.initials: DR
authors.lastname: Wolfram
authors.forename: M J
authors.initials: MJ
authors.lastname: Abdelkadir
authors.forename: J R
authors.initials: JR
authors.lastname: Lane
authors.forename: J
authors.initials: J
authors.lastname: Brussee
authors.forename: A P
authors.initials: AP
authors.lastname: Ijzerman
mesh_terms: D000179:Acrylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000179:Acrylates; C530636:HCAR2 protein, human; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; C036658:acrylic acid