title: Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta 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.
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor Campus, Ann Arbor, MI, 48105, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Belliotti
authors.forename: Thomas
authors.initials: T
authors.lastname: Capiris
authors.forename: I Victor
authors.initials: IV
authors.lastname: Ekhato
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Kinsora
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Field
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Heffner
authors.forename: Leonard T
authors.initials: LT
authors.lastname: Meltzer
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Schwarz
authors.forename: Charles P
authors.initials: CP
authors.lastname: Taylor
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Thorpe
authors.forename: Mark G
authors.initials: MG
authors.lastname: Vartanian
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Wise
authors.forename: Ti
authors.initials: T
authors.lastname: Zhi-Su
authors.forename: Mark L
authors.initials: ML
authors.lastname: Weber
authors.forename: David J
authors.initials: DJ
authors.lastname: Wustrow
mesh_terms: 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
chemical_list: 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