Synthesis and resolution of β-(aminomethyl)-4-chlorobenzeneethanesulfinic acid a potent gabaB receptor ligand

Carruthers, Nicholas I.; Spitler, James M.; Wong, Shing-Chun; Blythin, David J.; Chen, Xiao; Shue, Ho‐Jane; Mittelman, Stanley

doi:10.1016/0960-894x(95)00016-m

Cited by 15 publications

(1 citation statement)

References 12 publications

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“…GABA analogues in which a sulphinic acid group replaces the carboxylic acid group of GABA have not previously been evaluated to any great extent. The sulphinic acid analogue of baclofen (‘siclofen’, Carruthers et al ., 1995 ) and some other 3‐aminopropyl sulphinic acids with a large lipophilic group in the 2‐position have properties very similar to baclofen with central side effects appearing at doses close to those inhibiting TLOSRs (unpublished own findings). We have synthesised 3‐aminopropyl sulphinates with small substituents in the 2‐position (for instance hydroxy and keto groups).…”

Section: Introductionmentioning

confidence: 99%

Effects of (2R)‐(3‐amino‐2‐fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxation in dogs and mechanism of hypothermic effects in mice

Lehmann

Holmberg

Bhatt

et al. 2005

British J Pharmacology

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1 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. 2 TLOSRs were reduced by 5578% after intragastric administration of AFPSiA at 14 mmol kg À1 and did not decrease further at higher doses. When evaluated 2 and 4 h after administration, the effect declined to 3776 and 1679%, respectively. Spontaneous swallowing was only significantly inhibited at 100 mmol kg À1 . 3 The oral availability of AFPSiA was 52717 and 7174% 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. 4 In rat brain membranes, AFPSiA was found to have ten times higher affinity for rat brain GABA B (K i ¼ 4774.4 nM) compared to GABA A (K i ¼ 430746 nM) binding sites. The compound was a full agonist at human recombinant GABA B(1a,2) receptors (EC 50 ¼ 130710 nM). In contrast, the metabolite AFPSoA was considerably more selective for binding to rat brain GABA A (K i ¼ 3773.1 nM) vs GABA B (K i ¼ 68007280 nM) receptors. 5 In the mouse, high doses (1-8 mmol kg À1 ) 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 À1 ). This effect was unaffected by the selective GABA B receptor antagonist CGP62349. AFPSoA (1 and 2 mmol kg À1 ) produced transient and moderate hypothermia while the hypothermic response was considerably larger at 4 mmol kg À1 . 6 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.

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Section: Introductionmentioning

confidence: 99%

Effects of (2R)‐(3‐amino‐2‐fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxation in dogs and mechanism of hypothermic effects in mice

Lehmann

Holmberg

Bhatt

et al. 2005

British J Pharmacology

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ChemInform Abstract: Synthesis and Resolution of β‐(Aminomethyl)‐4‐ chlorobenzeneethanesulfinic Acid ‐ a Potent GABAB Receptor Ligand.

Carruthers¹,

Spitler²,

Wong³

et al. 1995

ChemInform

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1995 sulfenic acids, sulfinic acids sulfenic acids, sulfinic acids (acyclic compounds) P 0420 -107Synthesis and Resolution of β-(Aminomethyl)-4-chlorobenzeneethanesulfinic Acid -a Potent GABAB Receptor Ligand.-The title compound (IV) is prepared in racemic form from the known GABAreceptor antagonist saclofen (I). Its resolution succeeds via the corresponding O-benzyl-protected N-hydroxysulfonamides using a Chiralcel OD column. GABA-receptor binding studies show that the (-)-enantiomer exhibits a higher biological activity than the (+)-enantiomer.-(CARRUTHERS, N. I.; SPITLER, J. M.; WONG, S.-C.; BLYTHIN, D. J.; CHEN, X.; SHUE, H.-J.; MITTELMAN, S.; Bioorg. Med. Chem. Lett. 5 (1995) 3, 237-240; Dep. Chem.

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Chemistry of GABAB Modulators

Froestl¹,

Mickel²

1997

The GABA Receptors

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Synthesis and resolution of β-(aminomethyl)-4-chlorobenzeneethanesulfinic acid a potent gabaB receptor ligand

Cited by 15 publications

References 12 publications

Effects of (2R)‐(3‐amino‐2‐fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxation in dogs and mechanism of hypothermic effects in mice

Effects of (2R)‐(3‐amino‐2‐fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxation in dogs and mechanism of hypothermic effects in mice

ChemInform Abstract: Synthesis and Resolution of β‐(Aminomethyl)‐4‐ chlorobenzeneethanesulfinic Acid ‐ a Potent GABAB Receptor Ligand.

Chemistry of GABAB Modulators

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