Structure−Activity Relationships of Pregabalin and Analogues That Target the α₂-δ Protein

Abstract

Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prepared and evaluated for their alpha(2)-delta binding affinity as demonstrated by their ability to inhibit binding of [(3)H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [(3)H]leucine into CHO cells, a measure of their ability to compete with the endogenous substrate at the system L transporter. Compounds were also assessed in vivo for their ability to promote anxiolytic, analgesic, and anticonvulsant actions. These studies suggest that distinct structure activity relationships exist for alpha(2)-delta binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.

Molecular Targets for Antiepileptic Drug Development

“…96,97 Recently, it has become apparent that the molecular targets for gabapentin and pregabalin are ␣2-␦ proteins, specifically ␣2-␦-1 and ␣2-␦-2. 98,99 The evidence supporting this concept has been reviewed. 55 At present, the exact way in which binding to these proteins protects against seizures is not fully understood.…”

Molecular targets versus models for new antiepileptic drug discovery

“…Interestingly, the structure-activity relationships for α2δ and system L transporter activity are distinct. Optimizing α2δ modulatory activity to produce an intrinsically superior anticonvulsant substance would not necessarily result in a clinically useful AED since system L transporter substrate activity must be retained (Belliotti et al, 2005). In contrast to in vitro screening approaches, animal test systems only select compounds that are inherently anticonvulsant and are able to access the relevant brain targets.…”

New horizons in the development of antiepileptic drugs: Innovative strategies

“…2). The structural requirements for α 2 -δ binding differ from those that confer system L substrate activity (Belliotti et al, 2005). Both S(+)-and R(−)-isobutyl GABA are system L substrates (IC 50 values for inhibition of [ 3 H]L-leucine uptake are 158 and 355 μM, respectively), but the S-enantiomer (pregabalin) binds to α 2 -δ with 10-fold greater affinity than the R-enantiomer.…”

“…Mutagenesis experiments have shown that the anticonvulsant binding site is probably confined to the α 2 protein and/or the external portion of the associated δ component (Brown and Gee, 1998;Wang et al, 1999). Recent structure-activity studies with a variety of compounds related to gabapentin and pregabalin suggest that high affinity binding to α 2 -δ is required for anticonvulsant activity with compounds structurally similar to these drugs (Bryans et al, 1998;Belliotti et al, 2005).…”