title: Synthesis and evaluation of (E)-2-(acrylamido)cyclohex-1-enecarboxylic acid derivatives as HCA1, HCA2, and HCA3 receptor agonists.
abstract: 2-(3-(Naphthalen-2-yl)propanamido)cyclohex-1-enecarboxylic acid and its 6-hydroxynaphthalen-2-yl analogue are well-known hydroxyl-carboxylic acid (HCA) receptor HCA2 agonists. A series of novel aryl derivatives of 2-amidocyclohex-1-ene carboxylic acid that contained rigidity elements, such as an E-double bond, triple bond, and trans or cis-substituted cyclopropane rings, instead of the saturated ethane linker in the amide part of the molecules were designed and synthesized, and the derivatives' potency for the activation of HCA1, HCA2, and HCA3 receptors by 3'-5'-cyclic adenosine monophosphate (cAMP) assay were evaluated. The SAR studies revealed that the rigidifying of appropriate molecules enabled modulation of the potency and selectivity of the HCA2 receptor activation.
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Olga
authors.initials: O
authors.lastname: Bobileva
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Rasma
authors.initials: R
authors.lastname: Bokaldere
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Vija
authors.initials: V
authors.lastname: Gailite
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Ilze
authors.initials: I
authors.lastname: Kaula
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Martins
authors.initials: M
authors.lastname: Ikaunieks
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Gunars
authors.initials: G
authors.lastname: Duburs
authors.affiliation: Biomedical Research and Study Centre, Ratsupites 1, Riga LV-1067, Latvia.
authors.forename: Ramona
authors.initials: R
authors.lastname: Petrovska
authors.affiliation: Biomedical Research and Study Centre, Ratsupites 1, Riga LV-1067, Latvia.
authors.forename: Ilona
authors.initials: I
authors.lastname: Mandrika
authors.affiliation: Biomedical Research and Study Centre, Ratsupites 1, Riga LV-1067, Latvia.
authors.forename: Janis
authors.initials: J
authors.lastname: Klovins
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia. Electronic address: einars@osi.lv.
authors.forename: Einars
authors.initials: E
authors.lastname: Loza
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic; D013329:Structure-Activity Relationship
chemical_list: D000178:Acrylamides; D003509:Cyclohexanecarboxylic Acids; C533610:HCAR1 protein, human; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic
keywords: 2-Acrylamidocyclohex-1-ene; Agonist; Dyslipidemia; GPR109A; HCA2; Niacin; cAMP