title: Advantageous safety profile of a dual selective alpha(2C) agonist/alpha(2A) antagonist antinociceptive agent.
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.
authors.affiliation: Department of Non-Clinical Development, UCB Pharma S.A., B-1420, Braine-l'Alleud, Belgium.
authors.forename: Annie
authors.initials: A
authors.lastname: Delaunois
authors.forename: Pierrette
authors.initials: P
authors.lastname: De Ron
authors.forename: Paul
authors.initials: P
authors.lastname: Dedoncker
authors.forename: Marie-Luce
authors.initials: ML
authors.lastname: Rosseels
authors.forename: Miranda
authors.initials: M
authors.lastname: Cornet
authors.forename: Eric
authors.initials: E
authors.lastname: Jnoff
authors.forename: Etienne
authors.initials: E
authors.lastname: Hanon
authors.forename: Michel
authors.initials: M
authors.lastname: Guyaux
authors.forename: Brigitte Olympe
authors.initials: BO
authors.lastname: Depelchin
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D003000:Clonidine / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D010080:Oxazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D010146:Pain / Q000188:drug therapy; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000700:Analgesics; D010080:Oxazoles; D003000:Clonidine
keywords: adrenoceptor; cardiovascular safety; dog; neuropathic pain; rat; α2C-AR agonist/α2A-AR antagonist