Advantageous safety profile of a dual selective alpha2C agonist/alpha2A antagonist antinociceptive agent
Delaunois, A; De Ron, P; Dedoncker, P; Rosseels, ML; Cornet, M; Jnoff, E; Hanon, E; Guyaux, M; Depelchin, BO
| HERO ID | 1998356 |
|---|---|
| In Press | No |
| Year | 2014 |
| Title | Advantageous safety profile of a dual selective alpha2C agonist/alpha2A antagonist antinociceptive agent |
| Authors | Delaunois, A; De Ron, P; Dedoncker, P; Rosseels, ML; Cornet, M; Jnoff, E; Hanon, E; Guyaux, M; Depelchin, BO |
| Journal | Fundamental and Clinical Pharmacology |
| Volume | 28 |
| Issue | 4 |
| Page Numbers | 423-438 |
| Abstract | 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. |
| Doi | 10.1111/fcp.12047 |
| Pmid | 24020399 |
| Wosid | WOS:000339498900007 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |
| Keyword | adrenoceptor; cardiovascular safety; dog; neuropathic pain; rat; alpha(2C)-AR agonist/alpha(2A)-AR antagonist |