Saclofen

Saclofen
Names
	IUPAC name 3-Amino-2-(4-chlorophenyl)propane-1-sulfonic acid
Identifiers
CAS Number	125464-42-8 ;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:91596;
ChemSpider	108949 ;
IUPHAR/BPS	1078;
PubChem CID	122150;
UNII	LRZ36BCQ1Y;
CompTox Dashboard (EPA)	DTXSID90903970 ;
	InChI InChI=1S/C9H12ClNO3S/c10-9-3-1-7(2-4-9)8(5-11)6-15(12,13)14/h1-4,8H,5-6,11H2,(H,12,13,14);
	SMILES C1=CC(=CC=C1C(CN)CS(=O)(=O)O)Cl;
Properties
Chemical formula	C9H12ClNO3S
Molar mass	249.71 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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	Infobox references

Saclofen is a competitive antagonist for the GABA_B receptor.[1] 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- voltage-gated calcium channels (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 K_ir 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 — K_ir 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 involving absence seizures (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 affected neurons). Possible therapeutic uses of saclofen are currently being researched.

Saclofen has two enantiomeric forms. The (R)-stereoisomer is the one that binds to the GABA_B receptor, whereas the (S)-stereoisomer does not.[2]

References

Rang, HP; MM Dale; JM Ritter; RJ Flower (2007). Rang and Dale's Pharmacology (6th ed.). Churchill Livingstone Elsevier. ISBN 978-0-443-06911-6.
Kerr, D. I. B; Ong, J.; Vaccher, C.; Berthelot, P.; Flouquet, N.; Vaccher, M.-P.; Debaert, M. (1996). "GABAB receptor antagonism by resolved (R)-saclofen in the guinea-pig ileum". European Journal of Pharmacology. 308 (3): R1–R2. doi:10.1016/0014-2999(96)00334-2. PMID 8858312.

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[1] Rang, HP; MM Dale; JM Ritter; RJ Flower (2007). Rang and Dale's Pharmacology (6th ed.). Churchill Livingstone Elsevier. ISBN 978-0-443-06911-6.

[2] Kerr, D. I. B; Ong, J.; Vaccher, C.; Berthelot, P.; Flouquet, N.; Vaccher, M.-P.; Debaert, M. (1996). "GABAB receptor antagonism by resolved (R)-saclofen in the guinea-pig ileum". European Journal of Pharmacology. 308 (3): R1–R2. doi:10.1016/0014-2999(96)00334-2. PMID 8858312.