Gabapentinoids: Difference between revisions

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~~{{Stub}}~~

[[File:GABA.svg|250px|thumbnail|Skeletal structure of the [[GABA|gamma-aminobutyric acid]] (GABA) molecule.]]

[[File:~~Gabapentinoidsstructure~~.~~png~~|250px|thumbnail|~~Diagram showing~~ the ~~structural similarities of~~ [[GABA|gamma-aminobutyric acid]] (GABA)~~, [[pregabalin]] and [[gabapentin]]~~.]]

'''Gabapentinoids''' are a chemical class of [[psychoactive substances]] derived from [[GABA|gamma-aminobutyric acid]] (GABA).{{citation needed}} Members of this class include [[gabapentin]], [[F-phenibut]], [[phenibut]] and [[pregabalin]].

'''Gabapentinoids''', also known as α2δ ligands, are a relatively small chemical class of [[psychoactive substances]] derived from [[GABA|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]].

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==Chemistry==

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>{{cite book | vauthors=((Wyllie, E.)) | date= 2012 | title=Wyllie’s treatment of epilepsy: principles and practice. | isbn=9781451153484}}</ref><ref name="Benzon2014">{{cite book | vauthors=((Benzon, H. T.)), ((Rathmell, J. P.)), ((Wu, C. L.)), ((Turk, D. C.)), ((Argoff, C. E.)), ((Hurley, R. W.)) | date= 2014 | title=Practical management of pain | publisher=Elsevier/Saunders | url=https://www.sciencedirect.com/science/book/9780323083409 | isbn=9780323170802}}</ref>

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.<ref name=":0">{{cite journal | vauthors=((Dooley, D. J.)), ((Taylor, C. P.)), ((Donevan, S.)), ((Feltner, D.)) | journal=Trends in Pharmacological Sciences | title=Ca2+ channel α2δ ligands: novel modulators of neurotransmission | volume=28 | issue=2 | pages=75–82 | date= February 2007 | url=https://linkinghub.elsevier.com/retrieve/pii/S0165614706002896 | issn=01656147 | doi=10.1016/j.tips.2006.12.006}}</ref>

==List of Gabapentinoids==

{| class="wikitable"

|-

! scope="col" |'''Compound'''

! scope="col" style="width: 50px;" |'''R3'''

! scope="col" |'''Structure'''

|-

|[[GABA]]||H||[[File:GABA.svg|200px]]

|-

|[[Pregabalin]]||CH2CH(CH3)2||[[File:Pregabalin.svg|200px]]

|-

|[[Gabapentin]]||C5H10||[[File:Gabapentin.svg|200px]]

|-

|[[Phenibut]]||C6H5||[[File:Phenibut.svg|200px]]

|-

|[[F-Phenibut]]||C6H4F||[[File:F-Phenibut.svg|200px]]

|-

|[[Baclofen]]||C6H4Cl||[[File:Baclofen.svg|200px]]

|}

==Pharmacology==

Gabapentinoids act by ~~blocking~~ α2δ subunit-containing voltage-dependent calcium [[receptor#Ion_channels|channels]] (VGCCs).{{~~citation needed~~}} While all gabapentinoids block the α2δ channels, they also have unique pharmacological characteristics such as enzyme inhibition.{{~~citation needed~~}}

Gabapentinoids act by inhibiting the α2δ subunit-containing voltage-dependent calcium [[receptor#Ion_channels|channels]] (VGCCs).<ref>{{cite journal | vauthors=((Patel, R.)), ((Dickenson, A. H.)) | journal=Pharmacology Research & Perspectives | title=Mechanisms of the gabapentinoids and α 2 δ -1 calcium channel subunit in neuropathic pain | volume=4 | issue=2 | pages=e00205 | date= April 2016 | url=https://onlinelibrary.wiley.com/doi/10.1002/prp2.205 | issn=20521707 | doi=10.1002/prp2.205}}</ref> While all gabapentinoids block the α2δ channels, they also have unique pharmacological characteristics such as enzyme inhibition.<ref>{{cite journal | vauthors=((Goldlust, A.)), ((Su, T.-Z.)), ((Welty, D. F.)), ((Taylor, C. P.)), ((Oxender, D. L.)) | journal=Epilepsy Research | title=Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA | volume=22 | issue=1 | pages=1–11 | date= September 1995 | url=https://linkinghub.elsevier.com/retrieve/pii/0920121195000289 | issn=09201211 | doi=10.1016/0920-1211(95)00028-9}}</ref> The gabapentinoids are selective in their binding to the α2δ VDCC subunit.<ref name="Benzon2014"/>

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.<ref name=":0" />

Pregabalin has demonstrated significantly greater potency (about 2.5-fold) than gabapentin in clinical studies.<ref>{{cite journal | vauthors=((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.)), ((Kreeft, P. van der)), ((Scherbaum, N.)) | journal=Psychotherapy and Psychosomatics | title=Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data | volume=80 | issue=2 | pages=118–122 | date= 2011 | issn=1423-0348 | doi=10.1159/000321079}}

</ref>

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.<ref name=":1">{{cite journal | vauthors=((Calandre, E. P.)), ((Rico-Villademoros, F.)), ((Slim, M.)) | journal=Expert Review of Neurotherapeutics | title=Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use | volume=16 | issue=11 | pages=1263–1277 | date= November 2016 | issn=1744-8360 | doi=10.1080/14737175.2016.1202764}}</ref> 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.<ref>{{cite journal | vauthors=((Bockbrader, H. N.)), ((Wesche, D.)), ((Miller, R.)), ((Chapel, S.)), ((Janiczek, N.)), ((Burger, P.)) | journal=Clinical Pharmacokinetics | title=A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin | volume=49 | issue=10 | pages=661–669 | date= October 2010 | issn=1179-1926 | doi=10.2165/11536200-000000000-00000}}</ref>

=~~=Examples==~~

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.<ref name=":1" />

*[[Baclofen]]

*[[F-Phenibut]]

*[[Gabapentin]]

*[[Phenibut]]

*[[Pregabalin]]

==See also==

*[[Responsible use]]

*[[Depressants]]

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==External links==

*[https://en.wikipedia.org/wiki/Gabapentinoid Gabapentinoid (Wikipedia)]

==References==

[[Category:Gabapentinoid|*]][[Category:~~Chemical class~~]]

[[Category:Chemical class]]

[[Category:Pharmacology]]

@@ Line 1: / Line 1: @@
-{{Stub}}
+[[File:GABA.svg|250px|thumbnail|Skeletal structure of the [[GABA|gamma-aminobutyric acid]] (GABA) molecule.]]
-[[File:Gabapentinoidsstructure.png|250px|thumbnail|Diagram showing the structural similarities of [[GABA|gamma-aminobutyric acid]] (GABA), [[pregabalin]] and [[gabapentin]].]]
-'''Gabapentinoids''' are a chemical class of [[psychoactive substances]] derived from [[GABA|gamma-aminobutyric acid]] (GABA).{{citation needed}} Members of this class include [[gabapentin]], [[F-phenibut]], [[phenibut]] and [[pregabalin]].
+'''Gabapentinoids''', also known as α<sub>2</sub>δ ligands, are a relatively small chemical class of [[psychoactive substances]] derived from [[GABA|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]].
@@ Line 9: / Line 8: @@
 ==Chemistry==
-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>{{cite book | vauthors=((Wyllie, E.)) | date= 2012 | title=Wyllie’s treatment of epilepsy: principles and practice. | isbn=9781451153484}}</ref><ref name="Benzon2014">{{cite book | vauthors=((Benzon, H. T.)), ((Rathmell, J. P.)), ((Wu, C. L.)), ((Turk, D. C.)), ((Argoff, C. E.)), ((Hurley, R. W.)) | date= 2014 | title=Practical management of pain | publisher=Elsevier/Saunders | url=https://www.sciencedirect.com/science/book/9780323083409 | isbn=9780323170802}}</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">{{cite journal | vauthors=((Dooley, D. J.)), ((Taylor, C. P.)), ((Donevan, S.)), ((Feltner, D.)) | journal=Trends in Pharmacological Sciences | title=Ca2+ channel α2δ ligands: novel modulators of neurotransmission | volume=28 | issue=2 | pages=75–82 | date= February 2007 | url=https://linkinghub.elsevier.com/retrieve/pii/S0165614706002896 | issn=01656147 | doi=10.1016/j.tips.2006.12.006}}</ref>
+==List of Gabapentinoids==
+{| class="wikitable"
+|-
+! scope="col" |'''Compound'''
+! scope="col" style="width: 50px;" |'''R<sub>3</sub>'''
+! scope="col" |'''Structure'''
+|-
+|[[GABA]]||H||[[File:GABA.svg|200px]]
+|-
+|[[Pregabalin]]||CH<sub>2</sub>CH(CH<sub>3</sub>)<sub>2</sub>||[[File:Pregabalin.svg|200px]]
+|-
+|[[Gabapentin]]||C<sub>5</sub>H<sub>10</sub>||[[File:Gabapentin.svg|200px]]
+|-
+|[[Phenibut]]||C<sub>6</sub>H<sub>5</sub>||[[File:Phenibut.svg|200px]]
+|-
+|[[F-Phenibut]]||C<sub>6</sub>H<sub>4</sub>F||[[File:F-Phenibut.svg|200px]]
+|-
+|[[Baclofen]]||C<sub>6</sub>H<sub>4</sub>Cl||[[File:Baclofen.svg|200px]]
+|}
 ==Pharmacology==
-Gabapentinoids act by blocking α2δ subunit-containing voltage-dependent calcium [[receptor#Ion_channels|channels]] (VGCCs).{{citation needed}} While all gabapentinoids block the α2δ channels, they also have unique pharmacological characteristics such as enzyme inhibition.{{citation needed}}
+Gabapentinoids act by inhibiting the α2δ subunit-containing voltage-dependent calcium [[receptor#Ion_channels|channels]] (VGCCs).<ref>{{cite journal | vauthors=((Patel, R.)), ((Dickenson, A. H.)) | journal=Pharmacology Research & Perspectives | title=Mechanisms of the gabapentinoids and α 2 δ -1 calcium channel subunit in neuropathic pain | volume=4 | issue=2 | pages=e00205 | date= April 2016 | url=https://onlinelibrary.wiley.com/doi/10.1002/prp2.205 | issn=20521707 | doi=10.1002/prp2.205}}</ref> While all gabapentinoids block the α2δ channels, they also have unique pharmacological characteristics such as enzyme inhibition.<ref>{{cite journal | vauthors=((Goldlust, A.)), ((Su, T.-Z.)), ((Welty, D. F.)), ((Taylor, C. P.)), ((Oxender, D. L.)) | journal=Epilepsy Research | title=Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA | volume=22 | issue=1 | pages=1–11 | date= September 1995 | url=https://linkinghub.elsevier.com/retrieve/pii/0920121195000289 | issn=09201211 | doi=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 name="Benzon2014"/>
+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>{{cite journal | vauthors=((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.)), ((Kreeft, P. van der)), ((Scherbaum, N.)) | journal=Psychotherapy and Psychosomatics | title=Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data | volume=80 | issue=2 | pages=118–122 | date= 2011 | issn=1423-0348 | doi=10.1159/000321079}}
+</ref>
+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 <small>L</small>-leucine and <small>L</small>-phenylalanine.<ref name=":1">{{cite journal | vauthors=((Calandre, E. P.)), ((Rico-Villademoros, F.)), ((Slim, M.)) | journal=Expert Review of Neurotherapeutics | title=Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use | volume=16 | issue=11 | pages=1263–1277 | date= November 2016 | issn=1744-8360 | doi=10.1080/14737175.2016.1202764}}</ref> 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.<ref>{{cite journal | vauthors=((Bockbrader, H. N.)), ((Wesche, D.)), ((Miller, R.)), ((Chapel, S.)), ((Janiczek, N.)), ((Burger, P.)) | journal=Clinical Pharmacokinetics | title=A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin | volume=49 | issue=10 | pages=661–669 | date= October 2010 | issn=1179-1926 | doi=10.2165/11536200-000000000-00000}}</ref>
-==Examples==
+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.<ref name=":1" />
-*[[Baclofen]]
-*[[F-Phenibut]]
-*[[Gabapentin]]
-*[[Phenibut]]
-*[[Pregabalin]]
 ==See also==
 *[[Responsible use]]
 *[[Depressants]]
@@ Line 29: / Line 53: @@
 ==External links==
 *[https://en.wikipedia.org/wiki/Gabapentinoid Gabapentinoid (Wikipedia)]
 ==References==
-[[Category:Gabapentinoid|*]][[Category:Chemical class]]
+[[Category:Chemical class]]
+[[Category:Pharmacology]]
+<references />