title: Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel GABA(A) receptor agonists.
abstract: A series of 6-aminonicotinic acid analogues have been synthesized and pharmacologically characterized at native and selected recombinant GABA(A) receptors. 6-Aminonicotinic acid (3) as well as 2- and 4-alkylated analogues (9-11, 14-16) display low to mid-micromolar GABA(A)R binding affinities to native GABA(A) receptors (K(i) 1.1-24 μM). The tetrahydropyridine analogue of 3 (22) shows low-nanomolar affinity (K(i) 0.044 μM) and equipotency as an agonist to GABA itself as well as the standard GABA(A) agonist isoguvacine. Cavities surrounding the core of the GABA binding pocket were predicted by molecular interaction field calculations and docking studies in a α1β2γ2 GABA(A) receptor homology model, and were confirmed by affinities of substituted analogues of 3. The tight steric requirements observed for the remarkably few GABA(A)R agonists reported to date is challenged by our findings. New openings for agonist design are proposed which potentially could facilitate the exploration of different pharmacological profiles within the GABA(A)R area.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors.forename: Jette G
authors.initials: JG
authors.lastname: Petersen
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Camperdown Campus, 2006 NSW, Australia.
authors.forename: Troels
authors.initials: T
authors.lastname: Sørensen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Damgaard
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Camperdown Campus, 2006 NSW, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK 2100 Copenhagen, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Bergmann
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK 2100 Copenhagen, Denmark. Electronic address: bfr@sund.ku.dk.
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
mesh_terms: D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009525:Niacin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058785:GABA-A Receptor Agonists; D008024:Ligands; D011963:Receptors, GABA-A; D009525:Niacin; C044559:6-aminonicotinic acid
keywords: 2-Aminonicotinic acid analogues; GABA-A receptor agonists; Structure–activity studies