CNS Drug Discovery & Therapy
(Track) P2Y12 RECEPTOR ANTAGONISTS: A NEW APPROACH FOR THE TREATMENT OF INFLAMMATORY AND NEUROPATHIC PAIN Beata Sperlagh Abstract: P2Y12 receptor (P2Y12R) antagonists, such as clopidogrel, are widely used
antithromobotic drugs in the clinical practice, which became blockbuster
drugs in the past years. In this study analgesic effects of a variety of
P2Y12R antagonists were assessed in rodent models of inflammatory,
neuropathic pain and on acute nociception in parallel with their activity to
block the recombinant human P2Y12R. All tested compounds, including the
potent and selective P2Y12R antagonist PSB-0739 dose-dependently alleviated
inflammatory pain and the majority of P2Y12R antagonists attenuated
neuropathic pain in the partial sciatic nerve ligation model. The rank order
of in vivo mED values were in rough correlation with the potency of the
compounds to antagonize human P2Y12R mediated inhibition of isoproterenol
induced cAMP accumulation. mRNA encoding P2Y12Rs and IL-1beta protein were
overexpressed in the hind paw and lumbar spinal cord following intraplantar
CFA injection. This was accompanied by the upregulation of TNF-alpha, IL-6
and IL-10 in the hind paw. The selective P2Y12R antagonist PSB-0739
attenuated CFA-induced expression of all analyzed cytokines in the hind paw
and of IL-1beta in spinal cord. No antagonist affected motor coordination.
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