Saclofen
Encyclopedia
Saclofen is a competitive antagonist
for the GABAB receptor. This drug is an analogue of the GABAB agonist Baclofen
. The GABAB 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 GABAB 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 affected neuron
s). Possible therapeutic
uses of saclofen are currently being researched.
Salofen has two enantiomer
ic forms. The R stereoisomer is the one that binds to the GABAB receptor, whereas the S stereoisomer does not.
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
for the GABAB receptor. This drug is an analogue of the GABAB agonist Baclofen
Baclofen
Baclofen is a derivative of gamma-aminobutyric acid . It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism....
. The GABAB 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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
is understandably modest, because G-proteins rely on an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
cascade
Biochemical cascade
A biochemical cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. There are several important biochemical cascade reactions in biochemistry, including the enzymatic cascades, such as the coagulation cascade and the complement system,...
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 GABAB 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
Ethosuximide
Ethosuximide is a succinimide anticonvulsant, used mainly in absence seizures.-Approved:It is approved for absence seizures. Ethosuximide is considered the first choice drug for treating absence seizures in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence...
, 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 neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s). Possible therapeutic
Pharmacotherapy
Pharmacotherapy is the treatment of disease through the administration of drugs. As such, it is considered part of the larger category of therapy....
uses of saclofen are currently being researched.
Salofen has two enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
ic forms. The R stereoisomer is the one that binds to the GABAB receptor, whereas the S stereoisomer does not.