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Effects of (2 R )‐(3‐amino‐2‐fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxation in dogs and mechanism of hypothermic effects in mice
Author(s) -
Lehmann Anders,
Holmberg Ann Aurell,
Bhatt Ulhas,
BremnerDanielsen Marianne,
Brändén Lena,
Elg Susanne,
Elebring Thomas,
Fitzpatrick Kevin,
Geiss William B,
Guzzo Peter,
Jensen Jorgen,
Jerndal Gunilla,
Mattsson Jan P,
Nilsson Karolina,
Olsson BrittMarie
Publication year - 2005
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706299
Subject(s) - agonist , chemistry , in vivo , metabolite , receptor , pharmacology , medicine , gabaa receptor , endocrinology , metabolism , biochemistry , biology , microbiology and biotechnology
The effects of the novel GABA analogue (2 R )‐(3‐amino‐2‐fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxations (TLOSRs) were studied in the dog. In addition, the GABA A /GABA B selectivity was determined in vitro and in vivo , and the pharmacokinetics and the metabolism of the compound were studied in the dog and rat. TLOSRs were reduced by 55±8% after intragastric administration of AFPSiA at 14 μ mol kg −1 and did not decrease further at higher doses. When evaluated 2 and 4 h after administration, the effect declined to 37±6 and 16±9%, respectively. Spontaneous swallowing was only significantly inhibited at 100 μ mol kg −1 . The oral availability of AFPSiA was 52±17 and 71±4% in the dog and rat, respectively. A fraction of AFPSiA was oxidised to the corresponding sulphonate, (2 R )‐(3‐amino‐2‐fluoropropyl)sulphonic acid (AFPSoA) after oral administration to the rat and dog. In rat brain membranes, AFPSiA was found to have ten times higher affinity for rat brain GABA B ( K i =47±4.4 n M ) compared to GABA A ( K i =430±46 n M ) binding sites. The compound was a full agonist at human recombinant GABA B(1a,2) receptors (EC 50 =130±10 n M ). In contrast, the metabolite AFPSoA was considerably more selective for binding to rat brain GABA A ( K i =37±3.1 n M ) vs GABA B ( K i =6800±280 n M ) receptors. In the mouse, high doses (1–8 mmol kg −1 ) of AFPSiA induced a rapid and mild hypothermia followed by a profound and sustained hypothermia at the higher doses tested (6 and 8 mmol kg −1 ). This effect was unaffected by the selective GABA B receptor antagonist CGP62349. AFPSoA (1 and 2 mmol kg −1 ) produced transient and moderate hypothermia while the hypothermic response was considerably larger at 4 mmol kg −1 . It is concluded that AFPSiA inhibits but does not abolish TLOSRs in the dog. High doses of the compound induce hypothermia in the mouse, which probably is attributable to activation of the GABA A receptor. The latter effect may be caused both by AFPSiA and its oxidised sulphonic acid metabolite AFPSoA.British Journal of Pharmacology (2005) 146 , 89–97. doi: 10.1038/sj.bjp.0706299