title: Novel, highly potent and in vivo active inhibitor of GABA transporter subtype 1 with anticonvulsant, anxiolytic, antidepressant and antinociceptive properties.
abstract: Since GABAergic dysfunction underlies a variety of neurological and psychiatric disorders, numerous strategies leading to the augmentation of GABAergic neurotransmission have been introduced. One of them is the inhibition of GABA reuptake from the synaptic cleft mediated by four plasma membrane GABA transporters (GAT1-4). GAT1 which is exclusively expressed in the brain is an interesting target for centrally acting drugs. In this research, pharmacological properties of a novel, highly potent and selective inhibitor of GAT1, the guvacine derivative named DDPM-2571, were assessed in vivo.
  
  
  
  Pharmacological effects and pharmacokinetics of intraperitoneally administered DDPM-2571 were assessed in CD-1 mice.
  
  
  
  DDPM-2571 was quickly distributed into the brain and was highly effective in the prevention of chemically-induced seizures (pentylenetetrazole and pilocarpine models) and 6-Hz convulsions. It demonstrated significant anxiolytic-like and antidepressant-like properties. DDPM-2571 had antinociceptive properties, both in the hot plate test and in the second phase of the formalin test. Within the dose range tested, it did not impair animals' motor skills, but it impaired cognition and potentiated scopolamine-induced cognitive deficits in the passive avoidance task.
  
  
  
  Due to GAT1 inhibition, DDPM-2571 is effective in mouse models of chemically-induced seizures, anxiety, depression, acute and tonic pain. At biologically active doses, it does not impair animals' motor skills, but it might induce memory deficits. Taken together, DDPM-2571 can be regarded as a promising lead structure in the search for new centrally acting drugs and a potent pharmacological tool to study the biological role of GAT1.
authors: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland. Electronic address: salat.kinga@gmail.com.
authors: Kinga
authors: K
authors: Sałat
authors: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland.
authors: Adrian
authors: A
authors: Podkowa
authors: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland.
authors: Natalia
authors: N
authors: Malikowska
authors: Department für Pharmazie - Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 München, Germany.
authors: Felix
authors: F
authors: Kern
authors: Department für Pharmazie - Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 München, Germany.
authors: Jörg
authors: J
authors: Pabel
authors: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland.
authors: Ewelina
authors: E
authors: Wojcieszak
authors: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland.
authors: Katarzyna
authors: K
authors: Kulig
authors: Department für Pharmazie - Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 München, Germany.
authors: Klaus T
authors: KT
authors: Wanner
authors: Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland.
authors: Beata
authors: B
authors: Strach
authors: Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland.
authors: Elżbieta
authors: E
authors: Wyska
mesh_terms: D000700:Analgesics / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D007262:Infusions, Intravenous; D007263:Infusions, Parenteral; D008297:Male; D051379:Mice; D009539:Nicotinic Acids / Q000008:administration & dosage* / Q000737:chemistry; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D012640:Seizures / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000700:Analgesics; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D000928:Antidepressive Agents; D050485:GABA Plasma Membrane Transport Proteins; D009539:Nicotinic Acids; C493414:Slc6a1 protein, mouse; C015910:guvacine
keywords: Anxiety; Brain exposure; DDPM-2571; Depression; Formalin (PubChem CID: 712); GABA transporter-1 inhibitors; Mouse models of seizures; Pain and amnesia; Pentylenetetrazole (PubChem CID: 5917); Pilocarpine hydrochloride (PubChem CID: 5910); Scopolamine butylbromide (PubChem CID: 6852391); Scopolamine hydrobromide (PubChem CID: 6603108); Tiagabine; Tiagabine (PubChem CID: 60648)