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Diagram showing the structural similarities of gamma-aminobutyric acid (GABA), pregabalin and gabapentin.

Gabapentinoids, also known as α2δ ligands, are a relatively small chemical class of psychoactive substances derived from gamma-aminobutyric acid (GABA).[citation needed] Members of this class include gabapentin, F-phenibut, phenibut and pregabalin.

Gabapentinoids are commonly prescribed for epilepsy, neuropathic pain, and restless legs syndrome. Subjective effects include sedation, muscle relaxation, and anxiety suppression.

Gabapentinoids can be dangerous when mixed with other depressants such as benzodiazepines, alcohol and opioids.


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.[1][2]

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.[3]


Gabapentinoids act by inhibiting the α2δ subunit-containing voltage-dependent calcium channels (VGCCs).[4] While all gabapentinoids block the α2δ channels, they also have unique pharmacological characteristics such as enzyme inhibition.[5] The gabapentinoids are selective in their binding to the α2δ VDCC subunit.[6]

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.[3]

Pregabalin has demonstrated significantly greater potency (about 2.5-fold) than gabapentin in clinical studies.[7]

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.[8] 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.[9]

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.[8]


See also

External links


  1. Elaine Wyllie; Gregory D. Cascino; Barry E. Gidal; Howard P. Goodkin (17 February 2012). Wyllie's Treatment of Epilepsy: Principles and Practice. Lippincott Williams & Wilkins. p. 423. ISBN 978-1-4511-5348-4.
  2. Honorio Benzon; James P. Rathmell; Christopher L. Wu; Dennis C. Turk; Charles E. Argoff; Robert W Hurley (11 September 2013). Practical Management of Pain. Elsevier Health Sciences. p. 1006. ISBN 978-0-323-17080-2.
  3. 3.0 3.1 Dooley DJ, Taylor CP, Donevan S, Feltner D (2007). "Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission". Trends Pharmacol. Sci. 28 (2): 75–82. doi:10.1016/ PMID 17222465.
  4. Patel, R., & Dickenson, A. H. (2016). Mechanisms of the gabapentinoids and α2δ‐1 calcium channel subunit in neuropathic pain. Pharmacology research & perspectives, 4(2).
  5. Goldlust, A., Su, T. Z., Welty, D. F., Taylor, C. P., & Oxender, D. L. (1995). Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. Epilepsy research, 22(1), 1-11.
  6. Honorio Benzon; James P. Rathmell; Christopher L. Wu; Dennis C. Turk; Charles E. Argoff; Robert W Hurley (11 September 2013). Practical Management of Pain. Elsevier Health Sciences. p. 1006. ISBN 978-0-323-17080-2.
  7. Schifano F, D'Offizi S, Piccione M, Corazza O, Deluca P, Davey Z, Di Melchiorre G, Di Furia L, Farré M, Flesland L, Mannonen M, Majava A, Pagani S, Peltoniemi T, Siemann H, Skutle A, Torrens M, Pezzolesi C, van der Kreeft P, Scherbaum N (2011). "Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data". Psychother Psychosom. 80 (2): 118–22. doi:10.1159/000321079. hdl:2299/9328. PMID 21212719. S2CID 11172830.
  8. 8.0 8.1 Calandre EP, Rico-Villademoros F, Slim M (2016). "Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use". Expert Rev Neurother. 16 (11): 1263–1277. doi:10.1080/14737175.2016.1202764. PMID 27345098. S2CID 33200190.
  9. Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P (2010). "A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin". Clin Pharmacokinet. 49 (10): 661–9. doi:10.2165/11536200-000000000-00000. PMID 20818832. S2CID 16398062.