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{{Short description|GABAB receptor antagonist}} |
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{{technical|date=January 2023}} |
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{{chembox |
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| verifiedrevid = 360226438 |
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|ImageFile=Saclofen.png |
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| verifiedrevid = 449586524 |
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| ImageFile = Saclofen.svg |
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|IUPACName=3-amino-2-(4-chlorophenyl)propane-1-sulfonic acid |
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| ImageSize = 200px |
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|OtherNames= |
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| IUPACName = 3-Amino-2-(4-chlorophenyl)propane-1-sulfonic acid |
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|Section1= {{Chembox Identifiers |
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| OtherNames = |
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| CASNo=125464-42-8 |
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| Section1 = {{Chembox Identifiers |
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| PubChem=122150 |
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| CASNo_Ref = {{cascite|correct|??}} |
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| CASNo = 125464-42-8 |
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| PubChem = 122150 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 108949 |
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| UNII = LRZ36BCQ1Y |
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| ChEBI = 91596 |
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| 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) |
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| IUPHAR_ligand = 1078 |
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| IUPHAR_ligand = 1078 |
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| SMILES=C1=CC(=CC=C1C(CN)CS(=O)(=O)O)Cl |
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| SMILES = C1=CC(=CC=C1C(CN)CS(=O)(=O)O)Cl |
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|Section2= {{Chembox Properties |
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| Section2 = {{Chembox Properties |
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| C=9 |
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| Formula=C<sub>9</sub>H<sub>12</sub>ClNO<sub>3</sub>S |
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| H=12 |
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| MolarMass=249.714 |
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| Cl=1 |
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| N=1 |
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| O=3 |
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| S=1 |
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|Section3= {{Chembox Hazards |
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| Section3 = {{Chembox Hazards |
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'''Saclofen''' is a competitive ] for the ]. This drug is an analogue of the GABA<sub>B</sub> agonist ]. The GABA<sub>B</sub> 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 ] is understandably modest, because G-proteins rely on an ] ] to alter ] while ] 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. |
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'''Saclofen''' is a competitive ] for the ].<ref>{{Cite book |author=Rang, HP |author2=MM Dale |author3=JM Ritter |author4=RJ Flower |title=Rang and Dale's Pharmacology |edition=6th |publisher=Churchill Livingstone Elsevier |date=2007 |isbn=978-0-443-06911-6}}</ref> This drug is an analogue of the GABA<sub>B</sub> agonist ]. The GABA<sub>B</sub> 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 ] is understandably modest, because G-proteins rely on an ] ] to alter ] while ] 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 ] currents. Both result in inhibitory effects. |
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However, in animal experiments, saclofen is paradoxically observed to have an ] effect. This is probably because GABA<sub>B</sub> 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 Ca<sup>2+</sup> 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 (], a T-type Ca<sup>2+</sup> 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 ]s). Possible ] uses of saclofen are currently being researched. |
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However, in animal experiments, saclofen is paradoxically observed to have an ] effect. This is probably because GABA<sub>B</sub> effect is coupled to excitation in the thalamo-cortical circuits — K<sub>ir</sub> coupling via Gβγ subunits is so strong that it lowers the threshold for ] 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 ]s (], a T-type Ca<sup>2+</sup> 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 ]s). Possible ] uses of saclofen are currently being researched. |
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{{double image|left|Saclofen-R.png|101|Saclofen-S.png|101|(''R'')-Saclofen|(''S'')-Saclofen}} |
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Salofen has two ]ic forms. The ''R'' stereoisomer is the one that binds to the GABA<sub>B</sub> receptor, whereas the ''S'' stereoisomer does not.<ref>{{cite journal |journal= European Journal of Pharmacology |volume= 308 |issue= 3 |year= 1996 |pages= R1-R2 |doi= 10.1016/0014-2999(96)00334-2 |title= GABAB receptor antagonism by resolved (''R'')-saclofen in the guinea-pig ileum |authors= Kerr, D. I. B; Ong, J.; Vaccher, C.; Berthelot, P.; Flouquet, N.; Vaccher, M.-P.; Debaert, M. |pmid=8858312}}</ref> |
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== References == |
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{{Reflist}} |
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Saclofen has two ]ic forms. The (''R'')-stereoisomer is the one that binds to the GABA<sub>B</sub> receptor, whereas the (''S'')-stereoisomer does not.<ref>{{cite journal |journal=European Journal of Pharmacology |volume=308 |issue=3 |year=1996 |pages=R1-R2 |doi=10.1016/0014-2999(96)00334-2 |title=GABAB receptor antagonism by resolved (''R'')-saclofen in the guinea-pig ileum |author=Kerr, D. I. B |author2=Ong, J. |author3=Vaccher, C. |author4=Berthelot, P. |author5=Flouquet, N. |author6=Vaccher, M.-P. |author7=Debaert, M. |pmid=8858312}}</ref> |
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==References== |
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==References== |
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{{reflist}} |
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{{Reflist|2}} |
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* Rang, HP, and MM Dale, JM Ritter, RJ Flower; '''Rang and Dale's Pharmacology 6th edition'''; Churchill Livingstone Elsevier, 2007; ISBN 9780443069116 |
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{{GABAergics}} |
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{{GABAergics}} |
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{{nervous-system-drug-stub}} |
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