Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta protein

Thomas R Belliotti; Thomas Capiris; I Victor Ekhato; Jack J Kinsora; Mark J Field; Thomas G Heffner; Leonard T Meltzer; Jacob B Schwarz; Charles P Taylor; Andrew J Thorpe; Mark G Vartanian; Lawrence D Wise; Ti Zhi-Su; Mark L Weber; David J Wustrow

doi:10.1021/jm049762l

Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta protein

J Med Chem. 2005 Apr 7;48(7):2294-307. doi: 10.1021/jm049762l.

Authors

Thomas R Belliotti¹, Thomas Capiris, I Victor Ekhato, Jack J Kinsora, Mark J Field, Thomas G Heffner, Leonard T Meltzer, Jacob B Schwarz, Charles P Taylor, Andrew J Thorpe, Mark G Vartanian, Lawrence D Wise, Ti Zhi-Su, Mark L Weber, David J Wustrow

Affiliation

¹ Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor Campus, Ann Arbor, MI, 48105, USA.

PMID: 15801823
DOI: 10.1021/jm049762l

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.

MeSH terms

Amines / antagonists & inhibitors
Amines / metabolism
Amino Acid Transport System L / metabolism*
Analgesics / chemical synthesis*
Analgesics / chemistry
Analgesics / pharmacology
Animals
Anti-Anxiety Agents / chemical synthesis*
Anti-Anxiety Agents / chemistry
Anti-Anxiety Agents / pharmacology
Anticonvulsants / chemical synthesis*
Anticonvulsants / chemistry
Anticonvulsants / pharmacology
Brain / metabolism
CHO Cells
Calcium Channels / metabolism*
Cricetinae
Cricetulus
Cyclohexanecarboxylic Acids / antagonists & inhibitors
Cyclohexanecarboxylic Acids / metabolism
Gabapentin
In Vitro Techniques
Leucine / antagonists & inhibitors
Leucine / metabolism
Male
Mice
Mice, Inbred DBA
Pregabalin
Protein Binding
Protein Subunits / metabolism
Rats
Structure-Activity Relationship
Swine
gamma-Aminobutyric Acid / analogs & derivatives*
gamma-Aminobutyric Acid / chemical synthesis*
gamma-Aminobutyric Acid / chemistry
gamma-Aminobutyric Acid / metabolism
gamma-Aminobutyric Acid / pharmacology

Substances

Amines
Amino Acid Transport System L
Analgesics
Anti-Anxiety Agents
Anticonvulsants
Calcium Channels
Cyclohexanecarboxylic Acids
Protein Subunits
Pregabalin
gamma-Aminobutyric Acid
Gabapentin
Leucine