4-Methylpregabalin is a drug developed by

Pfizer Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...

and related to

pregabalin Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic, and anxiolytic amino acid medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless legs syndrome, opioid withdrawal, generalized anx ...

, which similarly acts as an

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

with effectiveness against difficult to treat "atypical" pain syndromes such as

neuropathic pain Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuo ...

. The effectiveness of pregabalin and its older relative

gabapentin Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat neuropathic pain and also for partial seizures of epilepsy. It is a commonly used medication for the treatment of neuropath ...

against pain syndromes of this kind (which tend to respond poorly to other analgesic drugs) has led to their widespread use, and these drugs have subsequently been found to be useful for many other medical applications, including as

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

s and mood stabilisers. However these drugs are still of relatively low potency, and scientists have struggled for years to come up with an improvement on pregabalin, with increasing pressure to find a suitably improved replacement before the

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling discl ...

on pregabalin expired in 2018. While it was determined that the mechanism of action involves modulation of the α₂δ

calcium channel A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, which are a type of calcium channel regulated by changes in membrane potential. Some calcium chan ...

subunits ( 1 and 2), derivatives that appeared to be more potent and effective than pregabalin at this target when tested ''in vitro'', repeatedly turned out to be weak or inactive when tested in animals. Eventually it was discovered that pregabalin is actively transported across the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

by the system L neutral amino acid transporter protein, which usually functions to transport certain amino acids, including

leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-Car ...

valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deproton ...

and

isoleucine Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

, into the brain. This explained the previous failures, as most alterations to the pregabalin molecule which increase affinity for the α₂δ channels and therefore increase apparent potency in the test tube, were found to also dramatically reduce binding to the system L transporter, and with no assisted transport into the brain, blood–brain barrier penetration was minimal and the drugs were inactive in animals. However, after extensive searching it was discovered that one

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

of the relatively simple derivative 4-methylpregabalin, was both 4× higher in binding affinity to α₂δ channels than pregabalin, and also retained similar affinity for the system L transporter. This was tested in animals and as hoped, was found to have similar effectiveness to pregabalin as an analgesic and with around 2–3× the potency. It remains unclear at this stage whether (3''R'',4''R'')-4-methylpregabalin will now be further developed for medical use in humans however, given the recent development of several competing drugs from the same family which are much further advanced in clinical trials.

References

{{DEFAULTSORT:Methylpregabalin, 4- Analgesics Calcium channel blockers GABA analogues Gamma-Amino acids Drugs developed by Pfizer

See also

References