The effects of the novel
GABA analogue (2R)-(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 mumol 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 micromol 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, (2R)-(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 nM) compared to
GABA(A) (K(i) = 430 +/- 46 nM) binding sites. The compound was a full agonist at human recombinant
GABA(B(1a,2)) receptors (EC(50) = 130 +/- 10 nM). In contrast, the metabolite AFPSoA was considerably more selective for binding to rat brain
GABA(A) (K(i) = 37 +/- 3.1 nM) vs
GABA(B) (K(i) = 6800 +/- 280 nM) 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.