Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect

This study demonstrated that cyclomethyline (<b>2</b>) and the corresponding enantiomers (<i>R</i>)-(−)-<b>2</b> and (<i>S</i>)-(+)-<b>2</b>, displaying α_2C-adrenoreceptor (AR) agonism/α_2A-AR antagonism, similarly to allyphenyline (<b>1</b>) and its enantiomers, significantly decreased the naloxone-precipitated withdrawal symptoms in mice at very low doses. It also highlighted that such positive effects on morphine dependence can even be improved by additional serotoninergic 5-HT_1A receptor (5-HT_1A-R) activation. Indeed, <b>1</b> or the single (<i>S</i>)-(+)-<b>1</b>, <b>2</b>, or both its enantiomers, all behaving as α_2C-AR agonists/α_2A-AR antagonists/5-HT_1A-R agonists, alone and at the same low dose, improved morphine withdrawal syndrome and exerted a potent antidepressant-like effect. Therefore, considering the elevated comorbidity between opiate abuse and depressed mood and the benefit of these multifunctional compounds to both disorders, it is possible that they prove more efficacious and less toxic than a cocktail of drugs in managing opioid addiction

Exploring Multitarget Interactions to Reduce Opiate Withdrawal Syndrome and Psychiatric Comorbidity

Opioid addiction is often characterized as a chronic relapsing condition due to the severe somatic and behavioral signs, associated with depressive disorders, triggered by opiate withdrawal. Since prolonged abstinence remains a major challenge, our interest has been addressed to such objective. Exploring multitarget interactions, the present investigation suggests that <b>3</b> or its (<i>S</i>)-enantiomer and <b>4</b>, endowed with effective α_2C-AR agonism/α_2A-AR antagonism/5-HT_1A-R agonism, or <b>7</b> and <b>9</b>–<b>11</b> producing efficacious α_2C-AR agonism/α_2A-AR antagonism/I₂–IBS interaction might represent novel multifunctional tools potentially useful for reducing withdrawal syndrome and associated depression. Such agents, lacking in sedative side effects due to their α_2A-AR antagonism, might afford an improvement over current therapies with clonidine-like drugs