Pregabalin is a potent and selective ligand for α2δ-1 and α2δ-2 calcium channel subunits

Abstract Pregabalin, a synthetic branched chain γ-amino acid with anticonvulsant, anxiolytic, and analgesic activities, has been shown to bind with high affinity to the voltage-gated calcium channel α 2 δ subunit. Given the broad therapeutic utility of pregabalin, a series of experiments was undertaken to determine the potency, selectivity, and specificity of pregabalin's receptor-binding profile at α 2 δ-1 and α 2 δ-2 subunits of voltage-gated calcium channels along with 38 widely studied receptors and channels. Receptor autoradiography was used to assess regional-binding density of pregabalin throughout the rat spinal cord and brain. In addition, a series of studies using in vivo electrophysiological recordings of γ-aminobutyric acid (GABA) A - and GABA B -evoked currents was undertaken to determine the interaction of pregabalin with GABAergic receptor subtypes. Together, the results of these studies demonstrate potent and selective binding of pregabalin to α 2 δ-1 and α 2 δ-2 subunits in native and recombinant human and porcine systems. Pregabalin did not interact with any of the 38 receptors and ion channels evaluated, and a variety of central nervous system (CNS)-targeted therapeutic drugs did not show activity at the α 2 δ subunits of voltage-gated calcium channels. Receptor autoradiography demonstrated extensive [ 3 H]-pregabalin binding throughout the CNS, with high-level binding in the cortex, hippocampus, cerebellum, dorsal horn of the spinal cord, and amygdala. Finally, receptor-binding and electrophysiological techniques failed to show evidence of an interaction between pregabalin and GABA A or GABA B receptors. These studies suggest that the clinical effects of pregabalin are likely due to direct and selective interactions with α 2 δ-1 and α 2 δ-2 subunits of voltage-gated calcium channels.