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Gabapentinoids, also known as α2δ ligands, are a relatively small chemical class of psychoactive substances derived from gamma-aminobutyric acid (GABA). Members of this class include gabapentin, F-phenibut, phenibut and pregabalin.
Gabapentinoids are close structural relatives, and are all 3-substituted derivatives of GABA, the differences being the addition of a cyclohexyl group on the GABA chain in the case of gabapentin, the substitution of that cyclohexyl group for an isobutyl group in the case of pregabalin, and the substitution of that isobutyl group with a cyclic phenyl ring in the case of phenibut. Hence, they are GABA analogues, as well as γ-amino acids.
Gabapentinoids closely resemble the α-amino acids L-leucine and L-isoleucine, and this may be of greater relevance in relation to their pharmacodynamics than their structural similarity to GABA.
Gabapentinoids act by inhibiting the α2δ subunit-containing voltage-dependent calcium channels (VGCCs). While all gabapentinoids block the α2δ channels, they also have unique pharmacological characteristics such as enzyme inhibition. The gabapentinoids are selective in their binding to the α2δ VDCC subunit.
The endogenous α-amino acids L-leucine and L-isoleucine, which closely resemble the gabapentinoids in chemical structure, are apparent ligands of the α2δ VDCC subunit with similar affinity as gabapentin and pregabalin, and are present in human cerebrospinal fluid at micromolar concentrations.
Pregabalin has demonstrated significantly greater potency (about 2.5-fold) than gabapentin in clinical studies.
Gabapentin and pregabalin are absorbed from the intestines by an active transport process mediated via the large neutral amino acid transporter 1 (LAT1, SLC7A5), a transporter for amino acids such as L-leucine and L-phenylalanine. The oral bioavailability of gabapentin is approximately 80% at 100 mg administered three times daily once every 8 hours, but decreases to 60% at 300 mg, 47% at 400 mg, 34% at 800 mg, 33% at 1,200 mg, and 27% at 1,600 mg, all with the same dosing schedule.
Gabapentin, pregabalin, and phenibut all undergo little or no metabolism. Conversely, gabapentin enacarbil, which acts as a prodrug of gabapentin, must undergo enzymatic hydrolysis to become active. This is done via non-specific esterases in the intestines and to a lesser extent in the liver.
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