The a2C adrenergic receptor (AR) subtype is involved in many central nervous system processes and contributes to spinal analgesic actions.[1] In this context, new agonists discriminating a2C-AR from a2A-AR open up the perspective of drug discovery for robust analgesia without cardiovascular and sedative side-effects.[2] Chemical modulation around 2-amino-oxazoline 1  led to the identification of selective a2C-AR agonists [3] but hampered by in vitro and in vivo genotoxicity. The general approach of capturing structure-genotoxicity relationships to get rid of this liability will be depicted. In particular, identification of key structural features responsible for genotoxicity was realized. From these efforts, a new back up chemical series 2  was identified overcoming genotoxicity issues related to scaffold 1  .References [1] J. Pharmacol. Exp. Ther. 2002  , 282-90.[2] J. Med. Chem. 2010  , 7825-32.[3] ChemMedChem,  2012  , 385-90.Acknowledgements The present project was supported by Walloon Region grant - DG06 (Convention n� 5601)

Structure genotoxicity relationships of selective alpha2C-AR agonists

244th National Meeting (2012)

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