4-Methylpregabalin: Difference between revisions

| verifiedrevid = 451933369

| IUPAC_name = (3R,4R)-3-aminomethyl-4,5-dimethylhexanoic acid

| image = 4-methylpregabalin structure.png

| CAS_number = <!-- blanked - oldvalue: 313651-25-1 -->

| molecular_weight = 173.252 g/mol

| smiles = O=C(O)CC(CN)C(C)C(C)C

| InChI = 1/C9H19NO2/c1-6(2)7(3)8(5-10)4-9(11)12/h6-8H,4-5,10H2,1-3H3,(H,11,12)/t7-,8+/m1/s1

| InChIKey = IASDTUBNBCYCJG-SFYZADRCBI

'''4-Methylpregabalin''' is a drug developed by [[Pfizer]] and related to [[pregabalin]], which similarly acts as an [[analgesic]] with effectiveness against difficult to treat "atypical" pain syndromes such as [[neuropathic pain]]. The effectiveness of pregabalin and its older relative [[gabapentin]] against these kind of pain syndromes (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]]s, [[muscle relaxant]]s, [[anxiolytic]]s and [[mood stabiliser]]s.

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]] on pregabalin expires in 2013. While it was determined that the mechanism of action involves modulation of the α₂δ [[calcium channel]]s ([[CACNA2D1|1]] and [[CACNA2D2|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]] by the system L [[neutral amino acid transporter]] protein, which usually functions to transport certain amino acids, including [[leucine]], [[valine]] and [[isoleucine]], 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]] of the relatively simple derivative 4-methylpregabalin, was both 4x 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 2-3x the potency.<ref name="pmid15801823">{{cite journal |author=Belliotti TR, Capiris T, Ekhato IV, Kinsora JJ, Field MJ, Heffner TG, Meltzer LT, Schwarz JB, Taylor CP, Thorpe AJ, Vartanian MG, Wise LD, Zhi-Su T, Weber ML, Wustrow DJ |title=Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta protein |journal=Journal of Medicinal Chemistry |volume=48 |issue=7 |pages=2294–307 |year=2005 |month=April |pmid=15801823 |doi=10.1021/jm049762l |url=}}</ref>

It remains unclear at this stage whether (3R,4R)-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.

[[Category:Pfizer]]