Might Allyphenyline and Cyclomethyline Become Profitable Multifunctional Tools in the Opioid Addiction Management?

Opioid addiction, termed a “chronic, relapsing disease”, is associated with a myriad of health and social problems and its management is an extremely important area of research. alpha-2-Adrenoreceptors (alpha-2-ARs), belonging to the superfamily of G-protein coupled receptors, have been demonstrated to be extremely sensitive to opioid exposure and to play a key role in opiate withdrawal symptoms. In detoxification alpha-2-AR agonists, such as clonidine and lofexidine, are often clinically used to reduce the intensity of withdrawal symptoms. However, the activation of the alpha-2A-AR subtype, triggered by these compounds, is responsible for evoked sedation and hypotension side effects. Therefore, selective alpha-2C-AR agonists, devoid of the side effects induced by the alpha-2A-AR stimulation, alone or in combination with opioids might represent an improvement over current therapies with clonidine-like drugs. Interestingly, depending on their preferred extended molecular conformation, allyphenyline (1) and its analogue cyclomethyline (2) behave as alpha-2C-AR agonists/alpha-2A-AR antagonists.1 Due to such a biological profile, 12 and 2 prove to be devoid of sedative effect as well as to prevent and contrast morphine dependence at very low dose (0.05 mg/Kg) in mice. Elevate comorbidity between opioid addiction and depression emerges from several clinical studies. It is noteworthy that, unlike the clinically used clonidine, 1 and 2 are able to provide alone and at the same low dose (0.05 mg/Kg) both improvement of morphine withdrawal symptoms and potent antidepressant-like effect. The study of the enantiomers of 1 and 2 highlights that the antidepressant response is associated with an additional 5-HT1A receptor (5-HT1A-R) activation. 1 and 2 display favourable in vitro ADME profiles and negligible activity on the hERG channel.