Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta protein.
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.
Belliotti
Thomas R
TR
Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor Campus, Ann Arbor, MI, 48105, USA.
Capiris
Thomas
T
Ekhato
I Victor
IV
Kinsora
Jack J
JJ
Field
Mark J
MJ
Heffner
Thomas G
TG
Meltzer
Leonard T
LT
Schwarz
Jacob B
JB
Taylor
Charles P
CP
Thorpe
Andrew J
AJ
Vartanian
Mark G
MG
Wise
Lawrence D
LD
Zhi-Su
Ti
T
Weber
Mark L
ML
Wustrow
David J
DJ
D000588:Amines / Q000037:antagonists & inhibitors / Q000378:metabolism; D027062:Amino Acid Transport System L / Q000378:metabolism*; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D015220:Calcium Channels / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D003509:Cyclohexanecarboxylic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077206:Gabapentin; D066298:In Vitro Techniques; D007930:Leucine / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D000069583:Pregabalin; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013552:Swine; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D000588:Amines; D027062:Amino Acid Transport System L; D000700:Analgesics; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D021122:Protein Subunits; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D007930:Leucine