Advantageous safety profile of a dual selective alpha(2C) agonist/alpha(2A) antagonist antinociceptive agent.

A selective α2C -adrenoceptor (AR) agonist was developed for the treatment of neuropathic pain. The objective was to dissociate analgesic activity from cardiovascular and sedative side effects commonly observed with nonselective agents. A 2-amino-oxazoline derivative (compound A), identified as a dual α2C -AR agonist/α2A -AR antagonist in in vitro-binding assays, exhibited in vivo efficacy in rodent pain models. Its safety profile was compared with that of clonidine in six different in vivo models. Contrary to clonidine, compound A did not induce hypotension in pentobarbital-anesthetized rats, in conscious spontaneous hypertensive rats, or in telemetered dogs. Both agents induced similar dose-dependent decreases in heart rate in dogs and rats. In anesthetized pithed rats, clonidine showed dose-dependent hypertension and inhibited electrical nerve stimulation-induced tachycardia at doses close to its efficacious doses in the mouse formalin test, while compound A had much weaker vasoconstrictive and antichronotropic effects. Finally, in a mouse Irwin test, no sedation was observed with compound A at 30-fold its ED50 in the mouse formalin test, while sedative effects of clonidine started from three-fold its ED50 . These data confirm the advantageous safety profile of the new dual α2C -AR agonist/α2A -AR antagonist agent vs. the nonselective agonist clonidine.