Gabapentinoids, also known as α2δ ligands, are a class of drugs that are derivatives of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) (i.e., GABA analogues) which block α2δ subunit-containing voltage-dependent calcium channels (VDCCs). This site has been referred to as the gabapentin receptor (α2δ subunit), as it is the target of the drugs gabapentin and pregabalin.
Clinically used gabapentinoids include gabapentin, pregabalin, and mirogabalin, as well as a gabapentin prodrug, gabapentin enacarbil. Additionally, phenibut has been found to act as a gabapentinoid in addition to its action of functioning as a GABAB receptor agonist. Further analogues like imagabalin are in clinical trials but have not yet been approved. Other gabapentinoids which are used in scientific research but have not been approved for medical use include atagabalin, 4-methylpregabalin and PD-217,014.
Medical uses
Gabapentinoids are approved for the treatment of epilepsy, postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy, fibromyalgia, generalized anxiety disorder, and restless legs syndrome. Some off-label uses of gabapentinoids include the treatment of insomnia, migraine, social phobia, panic disorder, mania, bipolar disorder, and alcohol withdrawal. Existing evidence on the use of gabapentinoids in chronic lower back pain is limited, and demonstrates significant risk of adverse effects, without any demonstrated benefit. The main side-effects include: a feeling of sleepiness and tiredness, decreased blood pressure, nausea, vomiting and also glaucomatous visual hallucinations.
Side effects
Pharmacology
Pharmacodynamics
Gabapentinoids are ligands of the auxiliary α2δ subunit site of certain , and thereby act as inhibitors of α2δ subunit-containing VDCCs. There are two drug-binding α2δ subunits, α2δ-1 and α2δ-2, and the gabapentinoids show similar affinity for (and hence lack of selectivity between) these two sites. The gabapentinoids are selective in their binding to the α2δ VDCC subunit. However, phenibut uniquely also binds to and acts as an agonist of the GABAB receptor with lower affinity (~5- to 10-fold in one study). Despite the fact that gabapentinoids are GABA analogues, gabapentin and pregabalin do not bind to the GABA receptors, do not convert into or GABA receptor agonists in vivo, and do not modulate GABA transport or metabolism. There is currently no evidence that the relevant actions of gabapentin and pregabalin are mediated by any mechanism other than inhibition of α2δ-containing VDCCs. Although, gabapentinoids such as gabapentin, but not pregabalin, have been found to activate Kv voltage-gated potassium channels (KCNQ).
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 (e.g., IC50 = 71 nM for L-isoleucine), and are present in human cerebrospinal fluid at micromolar concentrations (e.g., 12.9 μM for L-leucine, 4.8 μM for L-isoleucine). It has been hypothesized that they may be the endogenous ligands of the subunit and that they may competitively antagonize the effects of gabapentinoids. In accordance, while gabapentin and pregabalin have nanomolar affinities for the α2δ subunit, their potencies in vivo are in the low micromolar range, and competition for binding by endogenous L-amino acids has been said to likely be responsible for this discrepancy.
In one study, the affinity (Ki) values of gabapentinoids for the α2δ subunit expressed in rat brain were found to be 0.05 μM for gabapentin, 23 μM for (R)-phenibut, 39 μM for (S)-phenibut, and 156 μM for baclofen. Their affinities (Ki) for the GABAB receptor were >1 mM for gabapentin, 92 μM for (R)-phenibut, >1 mM for (S)-phenibut, and 6 μM for baclofen. Based on the low affinity of baclofen for the α2δ subunit relative to the GABAB (26-fold difference), its affinity for the α2δ subunit is unlikely to be of pharmacological importance.
Pregabalin has demonstrated significantly greater potency (about 2.5-fold) than gabapentin in clinical studies.