Pregabalin is a potent and selective ligand for α(2)δ-1 and α(2)δ-2 calcium channel subunits.

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.

Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects.

Matrix metalloproteinase-13 (MMP13) is a Zn(2+)-dependent protease that catalyzes the cleavage of type II collagen, the main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation in osteoarthritis, making this protease an attractive therapeutic target. However, clinically tested MMP inhibitors have been associated with a painful, joint-stiffening musculoskeletal side effect that may be due to their lack of selectivity. In our efforts to develop a disease-modifying osteoarthritis drug, we have discovered MMP13 inhibitors that differ greatly from previous MMP inhibitors; they do not bind to the catalytic zinc ion, they are noncompetitive with respect to substrate binding, and they show extreme selectivity for inhibiting MMP13. By structure-based drug design, we generated an orally active MMP13 inhibitor that effectively reduces cartilage damage in vivo and does not induce joint fibroplasias in a rat model of musculoskeletal syndrome side effects. Thus, highly selective inhibition of MMP13 in patients may overcome the major safety and efficacy challenges that have limited previously tested non-selective MMP inhibitors. MMP13 inhibitors such as the ones described here will help further define the role of this protease in arthritis and other diseases and may soon lead to drugs that safely halt cartilage damage in patients.