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Gabapentinoids: Difference between revisions
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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.<ref>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.</ref><ref>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.</ref> | 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.<ref>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.</ref><ref>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.</ref> | ||
Gabapentinoids closely resemble the α-amino acids <small>L</small>-leucine and <small>L</small>-isoleucine, and this may be of greater relevance in relation to their pharmacodynamics than their structural similarity to GABA.<ref>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/j.tips.2006.12.006. <nowiki>PMID 17222465</nowiki>.</ref> | Gabapentinoids closely resemble the α-amino acids <small>L</small>-leucine and <small>L</small>-isoleucine, and this may be of greater relevance in relation to their pharmacodynamics than their structural similarity to GABA.<ref name=":0">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/j.tips.2006.12.006. <nowiki>PMID 17222465</nowiki>.</ref> | ||
==Pharmacology== | ==Pharmacology== | ||
Gabapentinoids act by inhibiting the α2δ subunit-containing voltage-dependent calcium [[receptor#Ion_channels|channels]] (VGCCs).<ref>Patel, R., & Dickenson, A. H. (2016). Mechanisms of the gabapentinoids and α2δ‐1 calcium channel subunit in neuropathic pain. Pharmacology research & perspectives, 4(2).https://doi.org/10.1002/prp2.205</ref> While all gabapentinoids block the α2δ channels, they also have unique pharmacological characteristics such as enzyme inhibition.<ref>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.https://doi.org/10.1016/0920-1211(95)00028-9</ref> | Gabapentinoids act by inhibiting the α2δ subunit-containing voltage-dependent calcium [[receptor#Ion_channels|channels]] (VGCCs).<ref>Patel, R., & Dickenson, A. H. (2016). Mechanisms of the gabapentinoids and α2δ‐1 calcium channel subunit in neuropathic pain. Pharmacology research & perspectives, 4(2).https://doi.org/10.1002/prp2.205</ref> While all gabapentinoids block the α2δ channels, they also have unique pharmacological characteristics such as enzyme inhibition.<ref>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.https://doi.org/10.1016/0920-1211(95)00028-9</ref> The gabapentinoids are selective in their binding to the α<sub>2</sub>δ VDCC subunit.<ref>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 <bdi>978-0-323-17080-2</bdi>.</ref> | ||
The endogenous α-amino acids <small>L</small>-leucine and <small>L</small>-isoleucine, which closely resemble the gabapentinoids in chemical structure, are apparent ligands of the α<sub>2</sub>δ VDCC subunit with similar affinity as gabapentin and pregabalin, and are present in human cerebrospinal fluid at micromolar concentrations.<ref name=":0" /> | |||
Pregabalin has demonstrated significantly greater potency (about 2.5-fold) than gabapentin in clinical studies.<ref>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. <nowiki>PMID 21212719</nowiki>. S2CID 11172830.</ref> | |||
==Examples== | ==Examples== | ||