title: Synthesis and evaluation of N-substituted nipecotic acid derivatives with an unsymmetrical bis-aromatic residue attached to a vinyl ether spacer as potential GABA uptake inhibitors.
abstract: γ-Amino butyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS). A malfunction of the GABAergic neurotransmission is connected to several neuronal disorders like epilepsy, Alzheimer's disease, neuropathic pain, and depression. One possibility to enhance GABA levels in the synaptic cleft is to inhibit mGAT1, one of the four known plasma membrane bound GABA transporters, which is considered the most important GABA transporter subtype, being in charge of the removal of GABA from the synaptic cleft after a neuronal impulse. Lipophilic derivatives of nipecotic acid like Tiagabine (Gabitril®), an approved drug used in add-on therapy of epilepsy, are known to inhibit uptake of mGAT1 with high subtype selectivity and affinity. We synthesized new N-substituted nipecotic acid derivatives with a vinyl ether spacer and an unsymmetrical bis-aromatic residue, which carries fluorine substituents at various positions of the aromatic ring-system. The new compounds were characterized with respect to their potency and subtype selectivity as mGAT1 inhibitors.
authors.affiliation: Ludwig-Maximilians-University Munich, Department Pharmacy, Center for Drug Research, Butenandtstr. 7, 81377 Munich, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Quandt
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001692:Biological Transport; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D058805:GABA Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009557:Nipecotic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014753:Vinyl Compounds / Q000737:chemistry; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D018696:Neuroprotective Agents; D009557:Nipecotic Acids; C493413:SLC6A1 protein, human; D014753:Vinyl Compounds; C100195:vinyl ether; D005680:gamma-Aminobutyric Acid