title: Different in vitro and in vivo profiles of substituted 3-aminopropylphosphinate and 3-aminopropyl(methyl)phosphinate GABA(B)  receptor agonists as inhibitors of transient lower oesophageal sphincter relaxation.
abstract: OBJECTIVE
  Gastro-oesophageal reflux is predominantly caused by transient lower oesophageal sphincter relaxation (TLOSR) and GABA(B) receptor stimulation inhibits TLOSR. Lesogaberan produces fewer CNS side effects than baclofen, which has been attributed to its affinity for the GABA transporter (GAT), the action of which limits stimulation of central GABA(B) receptors. To understand the structure-activity relationship for analogues of lesogaberan (3-aminopropylphosphinic acids), and corresponding 3-aminopropyl(methyl)phosphinic acids, we have compared representatives of these classes in different in vitro and in vivo models.
  
  
  METHODS
  The compounds were characterized in terms of GABA(B) agonism in vitro. Binding to GATs and cellular uptake was done using rat brain membranes and slices respectively. TLOSR was measured in dogs, and CNS side effects were evaluated as hypothermia in mice and rats.
  
  
  RESULTS
  3-Aminopropylphosphinic acids inhibited TLOSR with a superior therapeutic index compared to 3-aminopropyl(methyl)phosphinic acids. This difference was most likely due to differential GAT-mediated uptake into brain cells of the former but not latter. In agreement, 3-aminopropyl(methyl)phosphinic acids were much more potent in producing hypothermia in rats even when administered i.c.v.
  
  
  CONCLUSIONS
  An enhanced therapeutic window for 3-aminopropylphosphinic acids compared with 3-aminopropyl(methyl)phosphinic acids with respect to inhibition of TLOSR was observed and is probably mechanistically linked to neural cell uptake of the former but not latter group of compounds. These findings offer a platform for discovery of new GABA(B) receptor agonists for the treatment of reflux disease and other conditions where selective peripheral GABA(B) receptor agonism may afford therapeutic effects.
authors.affiliation: AstraZeneca R&D, Mölndal, SwedenNerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and University of Adelaide, South Australia, AustraliaDepartment of Paediatrics, Tampere University Hospital, FinlandBrain Research Center, Medical School, University of Tampere, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Lehmann
authors.affiliation: AstraZeneca R&D, Mölndal, SwedenNerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and University of Adelaide, South Australia, AustraliaDepartment of Paediatrics, Tampere University Hospital, FinlandBrain Research Center, Medical School, University of Tampere, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Antonsson
authors.affiliation: AstraZeneca R&D, Mölndal, SwedenNerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and University of Adelaide, South Australia, AustraliaDepartment of Paediatrics, Tampere University Hospital, FinlandBrain Research Center, Medical School, University of Tampere, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Aurell-Holmberg
authors.affiliation: AstraZeneca R&D, Mölndal, SwedenNerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and University of Adelaide, South Australia, AustraliaDepartment of Paediatrics, Tampere University Hospital, FinlandBrain Research Center, Medical School, University of Tampere, Finland.
authors.forename: L A
authors.initials: LA
authors.lastname: Blackshaw
authors.affiliation: AstraZeneca R&D, Mölndal, SwedenNerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and University of Adelaide, South Australia, AustraliaDepartment of Paediatrics, Tampere University Hospital, FinlandBrain Research Center, Medical School, University of Tampere, Finland.
authors.forename: L
authors.initials: L
authors.lastname: Brändén
authors.affiliation: AstraZeneca R&D, Mölndal, SwedenNerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and University of Adelaide, South Australia, AustraliaDepartment of Paediatrics, Tampere University Hospital, FinlandBrain Research Center, Medical School, University of Tampere, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Elebring
authors.affiliation: AstraZeneca R&D, Mölndal, SwedenNerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and University of Adelaide, South Australia, AustraliaDepartment of Paediatrics, Tampere University Hospital, FinlandBrain Research Center, Medical School, University of Tampere, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Jensen
authors.affiliation: AstraZeneca R&D, Mölndal, SwedenNerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and University of Adelaide, South Australia, AustraliaDepartment of Paediatrics, Tampere University Hospital, FinlandBrain Research Center, Medical School, University of Tampere, Finland.
authors.forename: L
authors.initials: L
authors.lastname: Kärrberg
authors.affiliation: AstraZeneca R&D, Mölndal, SwedenNerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and University of Adelaide, South Australia, AustraliaDepartment of Paediatrics, Tampere University Hospital, FinlandBrain Research Center, Medical School, University of Tampere, Finland.
authors.forename: J P
authors.initials: JP
authors.lastname: Mattsson
authors.affiliation: AstraZeneca R&D, Mölndal, SwedenNerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and University of Adelaide, South Australia, AustraliaDepartment of Paediatrics, Tampere University Hospital, FinlandBrain Research Center, Medical School, University of Tampere, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Nilsson
authors.affiliation: AstraZeneca R&D, Mölndal, SwedenNerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and University of Adelaide, South Australia, AustraliaDepartment of Paediatrics, Tampere University Hospital, FinlandBrain Research Center, Medical School, University of Tampere, Finland.
authors.forename: S S
authors.initials: SS
authors.lastname: Oja
authors.affiliation: AstraZeneca R&D, Mölndal, SwedenNerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and University of Adelaide, South Australia, AustraliaDepartment of Paediatrics, Tampere University Hospital, FinlandBrain Research Center, Medical School, University of Tampere, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Saransaari
authors.affiliation: AstraZeneca R&D, Mölndal, SwedenNerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and University of Adelaide, South Australia, AustraliaDepartment of Paediatrics, Tampere University Hospital, FinlandBrain Research Center, Medical School, University of Tampere, Finland.
authors.forename: S
authors.initials: S
authors.lastname: von Unge
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D049630:Esophageal Sphincter, Lower / Q000187:drug effects* / Q000502:physiology; D005260:Female; D058786:GABA-B Receptor Agonists / Q000494:pharmacology*; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009126:Muscle Relaxation / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology; D018080:Receptors, GABA-B / Q000502:physiology
chemical_list: D058786:GABA-B Receptor Agonists; D009943:Organophosphorus Compounds; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C061388:3-aminopropylphosphinic acid; C068457:3-aminopropyl(methyl)phosphinic acid