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 ~~class~~ of ~~chemical compounds~~ that are ~~derivatives~~ of [[GABA|~~gamma~~-~~aminobutyric acid~~]] ~~which block~~ α2δ subunit-containing voltage-dependent calcium [[receptor#Ion_channels|channels]]. While all gabapentinoids block the α2δ channels, they also have unique pharmacological characteristics such as enzyme inhibition.

'''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]].

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

==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>{{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 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>

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" />

==See also==

Gabapentinoids are commonly used for epilepsy, neuropathic pain, and [[restless legs syndrome]]. Gabapentinoids are often [[Sedation|sedating]], have [[Seizure suppression|anticonvulsant]] effects, and [[Anxiety suppression|suppress anxiety]]. Drugs in this class include [[gabapentin]], [[F-phenibut]], [[phenibut]] and, [[pregabalin]]. Gabapentinoids can be dangerous when mixed with other [[depressants]] such as [[benzodiazepine]]s, [[alcohol]] and [[opioid]]s.

~~=See also=~~

*[[Responsible use]]

*[[Depressants]]

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*[[Phenibut]]

*[[Pregabalin]]

==External links==

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

==References==

[[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 class of chemical compounds that are derivatives of [[GABA|gamma-aminobutyric acid]] which block α2δ subunit-containing voltage-dependent calcium [[receptor#Ion_channels|channels]]. While all gabapentinoids block the α2δ channels, they also have unique pharmacological characteristics such as enzyme inhibition.
+'''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]].
+Gabapentinoids can be dangerous when mixed with other [[depressants]] such as [[benzodiazepines]], [[alcohol]] and [[opioids]].
+==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>{{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 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>
+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" />
+==See also==
-Gabapentinoids are commonly used for epilepsy, neuropathic pain, and [[restless legs syndrome]]. Gabapentinoids are often [[Sedation|sedating]], have [[Seizure suppression|anticonvulsant]] effects, and [[Anxiety suppression|suppress anxiety]]. Drugs in this class include [[gabapentin]], [[F-phenibut]], [[phenibut]] and, [[pregabalin]]. Gabapentinoids can be dangerous when mixed with other [[depressants]] such as [[benzodiazepine]]s, [[alcohol]] and [[opioid]]s.
-=See also=
 *[[Responsible use]]
 *[[Depressants]]
@@ Line 10: / Line 51: @@
 *[[Phenibut]]
 *[[Pregabalin]]
+==External links==
+*[https://en.wikipedia.org/wiki/Gabapentinoid Gabapentinoid (Wikipedia)]
+==References==
+[[Category:Chemical class]]
+[[Category:Pharmacology]]
+<references />