Enantioselective interactions to improve adrenergic α2C-agonism/α2A-antagonism

Recently (1) we demonstrated that compounds 1 and 2 behaved as potent and selective α2C-AR agonists and effective α2A-AR antagonists. It is known that in clinical pain management, α2C selective agonists devoid of the sedative side effects associated with α2A-AR stimulation might represent alone or in combination with opioid analgesics an improvement over current therapies with clonidine-like drugs. Therefore, 1 and 2 co-administered with morphine were tested using the mouse tail-flick test. A very low dose (0.05 mg/kg) of both compounds caused a significant increase in morphine analgesia comparable to that obtained with a 0.5 mg/kg dose of clonidine. In addition, 1 and 2 were devoid of sedative side effects. This promising behaviour is being strengthened by the observation that 1 and 2 are endowed with good chemical stability and exibit high passive diffusion through an artificial phospholipid membrane (PAMPA), which could permit them to interact with their target at a non-surface exposed binding site. The presence of a stereocentre in 1 and 2 prompted us to investigate the stereochemical requirements for a possible α2C-AR agonism/α2A-AR antagonism improvement. Therefore, the novel R and S enantiomers of 1 and 2 were prepared and their biological profiles were determined by binding and functional assays. Moreover, their effects on morphine analgesia moduòlation were evaluated. In addition, for racemic compound 1 and its corresponding enantiomers (R)-(-)-1 and (S)-(+)-1 the study was also extended to the acquisition and expression of morphine tolerance and dependence. (1) Cardinaletti, C.; Mattioli, L.; Ghelfi, F.; Del Bello, F.; Giannella, M.; Buzzone, A.; Paris, H.; Perfumi, M.; Piergentili, A.; Quaglia, W.; Pigini, M. J. Med. Chem. 2009, 52, 7319-7322