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

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Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor Campus, Ann Arbor, MI, 48105, Sandwich Laboratories, Sandwich, Kent CT13 9NJ UK, Nagoya Laboratories, 5-2 Takatoy-Cho, Chita-gun Aichi, 470-2393 Japan
Cite this: J. Med. Chem. 2005, 48, 7, 2294–2307
Publication Date (Web):February 17, 2005
https://doi.org/10.1021/jm049762l
Copyright © 2005 American Chemical Society
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    Abstract

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    Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the α2-δ 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 α2-δ binding affinity as demonstrated by their ability to inhibit binding of [3H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [3H]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 α2-δ binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.

    †

     Michigan Laboratories.

    ‖

     Current address:  Kalexsyn, Inc., Kalamazoo, MI 49008.

    ⊥

     Current address:  Bristol-Myers Squibb Co., Princeton, NJ 08543.

    ‡

     Sandwich Laboratories.

    §

     Nagoya Laboratories.

    *

     To whom correspondence should be addressed. Pfizer Global Research and Development, 2800 Plymouth Rd., Ann Arbor, MI 48105. Phone 734-622-1377, e-mail [email protected].

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