Saclofen

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ImageFile=Saclofen.pngImageSize=200px
IUPACName=3-amino-2-(4-chlorophenyl)propane-1-sulfonic acid
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CASNo=125464-42-8
PubChem=122150
SMILES=C1=CC(=CC=C1C(CN)CS(=O)(=O)O)Cl
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Section2= Chembox Properties
Formula=C₉H₁₂ClNO₃S
MolarMass=249.714
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Saclofen is a competitive antagonist for the GABA_B receptor. This drug is an analogue of the GABA_B agonist Baclofen. The GABA_B receptor is heptahelical receptor, expressed as an obligate heterodimer, which couples to the Gi/o class of heterotrimeric G-proteins. The action of saclofen on the central nervous system is understandably modest, because G-proteins rely on an enzyme cascade to alter cell behavior while ionotropic receptors immediately change the ionic permeability of the neuronal plasma membrane, thus changing its firing patterns. These particular receptors, presynaptically inhibit N- and P/Q- VGCCs via a direct interaction of the dissociated beta gamma subunit of the g-protein with the intracellular loop between the 1st and 2nd domain of the VGCC's alpha-subunit; postsynaptically, these potentiate Kir currents. Both result in inhibitory effects.

However, in animal experiments, saclofen is paradoxically observed to have an antiepileptic effect. This is probably because GABA_B effect is coupled to excitation in the thalamo-cortical circuits - Kir coupling via Gβγ subunits is so strong that it lowers the threshold for T-type Ca2+ channel opening enough to elicit their opening, and thus an excitation in this circuit. Since thalamo-cortical circuit overfiring is seen in types of epilepsy such as absence epilepsy (Ethosuximide, a T-type Ca2+ channel blocker, is used in the treatment of this), the unexpected antiepileptic effects of saclofen may thus be explained (unexpected as the GABA receptors are inhibitory, and antagonizing them should lead to hyperactivity of the effected neurons). Possible therapeutic uses of saclofen are currently being researched.

References

*Rang, HP, and MM Dale, JM Ritter, RJ Flower; Rang and Dale's Pharmacology 6th edition; Churchill Livingstone Elsevier, 2007; ISBN 9780443069116