title: Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery.
abstract: Pregabalin (Lyrica) is a new antiepileptic drug that is active in animal seizure models. Pregabalin is approved in US and Europe for adjunctive therapy of partial seizures in adults, and also has been approved for the treatment of pain from diabetic neuropathy or post-herpetic neuralgia in adults. Recently, it has been approved for treatment of anxiety disorders in Europe. Pregabalin is structurally related to the antiepileptic drug gabapentin and the site of action of both drugs is similar, the alpha2-delta (alpha2-delta) protein, an auxiliary subunit of voltage-gated calcium channels. Pregabalin subtly reduces the synaptic release of several neurotransmitters, apparently by binding to alpha2-delta subunits, and possibly accounting for its actions in vivo to reduce neuronal excitability and seizures. Several studies indicate that the pharmacology of pregabalin requires binding to alpha2-delta subunits, including structure-activity analyses of compounds binding to alpha2-delta subunits and pharmacology in mice deficient in binding at the alpha2-delta Type 1 protein. The preclinical findings to date are consistent with a mechanism that may entail reduction of abnormal neuronal excitability through reduced neurotransmitter release. This review addresses the preclinical pharmacology of pregabalin, and also the biology of the high affinity binding site, and presumed site of action.
authors.affiliation: Department of CNS Biology, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. charles.taylor@pfizer.com
authors.forename: Charles P
authors.initials: CP
authors.lastname: Taylor
authors.forename: Timothy
authors.initials: T
authors.lastname: Angelotti
authors.forename: Eric
authors.initials: E
authors.lastname: Fauman
mesh_terms: D000588:Amines / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D015220:Calcium Channels / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D004828:Epilepsies, Partial / Q000188:drug therapy*; D004830:Epilepsy, Tonic-Clonic / Q000188:drug therapy; D000077206:Gabapentin; D008969:Molecular Sequence Data; D000069583:Pregabalin; D011487:Protein Conformation; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000588:Amines; D000927:Anticonvulsants; C512066:CACNA2D1 protein, mouse; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin