Synthesis and biological evaluation of conformationally restricted Gabapentin analogues.

A series of conformationally restricted Gabapentin analogues has been synthesised. The pyrrolidine analogue (R)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride (3a) had an IC50 of 120 nM, similar to that of Gabapentin (IC50 = 140 nM), at the Gabapentin binding site on the alpha2delta subunit of a calcium channel. Compound (3a) also reversed carrageenan induced hyperalgesia in rats.

An in vitro investigation into conformational aspects of gabapentin.

Conformational analysis of constrained cyclohexane systems was pioneered fifty years ago by Barton and Hassel. We now report an investigation based on a conformational analysis of a number of novel cyclohexane based Gabapentin analogues coupled with their in vitro evaluation at the Gabapentin binding site. These data are used to propose a possible binding conformation for Gabapentin.

3-substituted GABA analogs with central nervous system activity: a review.

Gabapentin and Pregabalin are both 3-alkylated gamma-amino butyric acid (GABA) analogs. Gabapentin was designed as a lipophilic GABA analog and was first synthesized as a potential anticonvulsant and was launched in 1994 as add-on therapy for the treatment of epilepsy. In this review the discovery and development of gabapentin as an anticonvulsant are discussed. During human trials and while in clinical use, it became apparent that gabapentin induced some other potentially useful therapeutic effects in chronic pain states and behavioral disorders. A review of animal and clinical data relating to these other potential therapeutic utilities is presented. Pregabalin was identified after an investigation into other 3-substituted GABA analogs. It has since been shown to have a similar pharmacological profile to gabapentin with greater potency in preclinical models of pain and epilepsy. Studies of the mechanism(s) of action of these compounds are discussed. Work towards identifying new analogs of both gabapentin and pregabalin is also reviewed.

Novel treatments for pain.

At present, the principal treatments for pain are non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, but both of these classes suffer from drawbacks in clinical use. Some of the NSAIDs are associated with gastric damage as well as kidney and liver toxicity, and an increase in blood clotting time, while the opioids can produce tolerance and dependence, along with constipation, nausea, respiratory depression and sedation. In certain cases, both NSAID and opioid use are ineffective. There are some other less commonly used treatments including local anesthetics, anticonvulsants and tricyclic antidepressants, but, many recent strategies have involved the search for other NSAIDs and opioids which lack the unwanted side-effects present in both classes of drug. More recently, in addition to the classical strategies, some novel approaches have started to produce compounds which have entered the clinic, including cyclooxygenase-2 (COX-2) inhibitors and modulators of the alpha2delta subunit of L-type calcium channels.

Identification of novel ligands for the gabapentin binding site on the alpha2delta subunit of a calcium channel and their evaluation as anticonvulsant agents.

As part of a program to investigate the structure-activity relationships of Gabapentin (Neurontin), a number of alkylated analogues were synthesized and evaluated in vitro for binding to the Gabapentin binding site located on the alpha2delta subunit of a calcium channel. A number of other bridged and heterocyclic analogues are also reported along with their in vitro data. Two compounds showing higher affinity than Gabapentin were selected for evaluation in an animal model of epilepsy. One of these compounds, cis-(1S,3R)-(1-(aminomethyl)-3-methylcyclohexyl)acetic acid hydrochloride (19), was shown to be effective in this model with a profile similar to that of Gabapentin itself.