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

Abstract

This study demonstrated that cyclomethyline (2) and the corresponding enantiomers (R)-(−)-2 and (S)-(+)-2, displaying α 2C -adrenoreceptor (AR) agonism/α 2A -AR antagonism, similarly to allyphenyline (1) 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, 1 or the single (S)-(+)-1, 2, 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. KEYWORDS: α 2 -adrenergic ligands, 5-HT 1A -R agonists, morphine withdrawal symptoms reduction, antidepressant-like effect M orphine use is the classical approach in the treatment of chronic or cancer-related pain. Nevertheless, even when legally allowed and closely monitored, long-term opioid administration alters central pain-related systems, inducing tolerance and dependence. Opioid addiction, termed a "chronic relapsing disease", is associated with a myriad of health and social problems; hence, its management is an extremely important area of research. 1 α 2 -Adrenoreceptors (α 2 -ARs), which have been demonstrated to be extremely sensitive to opioid exposure and to play a key role in opiate withdrawal symptoms, 2 belong to the superfamily of G-protein-coupled receptors. The three α 2A -, α 2B -, and α 2C -AR subtypes are widely distributed in the central nervous system (CNS) and peripheral tissues. 3 Studies with genetically engineered mice have demonstrated that the α 2A subtype mediates hypotension, sedation, and analgesia, as well as inhibition of monoamine release and metabolism in the brain. The α 2B subtype mediates vasoconstriction, while the α 2C subtype appears to be involved in many CNS processes, such as the startle reflex, stress responses, and control of locomotion as well as feedback inhibition of adrenal cathecolamine release. Moreover, in the brain, α 2A -and α 2C -ARs, as "heteroreceptors", inhibit dopamine and serotonin release. Finally, the α 2C subtype can contribute to adrenergic-opioid synergy and spinal α 2 -agonist-mediated analgesia. 3−5 In detoxification, α 2 -AR agonists such as clonidine and lofexidine are often clinically used alone or in combination with traditional treatments to reduce the intensity of withdrawal symptoms, thus increasing treatment duration. However, the α 2A -AR activation triggered by these compounds is responsible for side effects such as sedation and hypotension.

Exploring Multitarget Interactions to Reduce Opiate Withdrawal Syndrome and Psychiatric Comorbidity

“…22 These properties were maintained and even enhanced only by the (S)-(+)-3 enantiomer, whereas (R)-(−)-3 was endowed with negligible affinity (pK i < 5). Such behavior was analogous to that observed for 1 and its enantiomers, 9 and this similarity was also confirmed by the FST test.…”

“…This observation strengthened the previous result and unequivocally In addition, the low dose required also for 3 and its (S)-(+)-enantiomer, both endowed with efficacious dual α 2C -AR/5-HT 1A -R agonism, confirmed the already reported peculiar relationship between α 2C -AR activation and 5-HT function. 9 From the present study, it also emerged that the racemate 4 displayed high 5-HT 1A -R affinity and agonist potency (pK i = 7.86; pD 2 = 7.08; %E max = 118). Therefore, 3 or its (S)-enantiomer and 4 might, analogously to 1 and 2, represent novel and advantageous potential tools in managing opioid addiction and psychiatric comorbidity.…”

“…10 Experiments carried out in the presence of the α 2 -AR antagonist yohimbine and the 5-HT 1A -R antagonist WAY100135 suggested that dual α 2C -AR/5-HT 1A -R activation was required for the antidepressant-like effect induced by low doses of the aforementioned compounds. 9 On the other hand, the participation of 5-HT 1A -R in the antidepressant effect was supported by preclinical results suggesting that postsynaptic 5-HT 1A -Rs are particularly important in the antidepressant response. Moreover, behavioral models of stress and antidepressant drug effects in animals, such as the FST, indicated that the activation of postsynaptic 5-HT 1A -Rs induced changes similar to those of conventional antidepressants.…”

“…9 This effect was associated only with the (S)-(+)-enantiomer, whereas (R)-(−)-3, lacking in significant 5-HT 1A -R affinity, was inactive ( Figure 1A). This observation strengthened the previous result and unequivocally In addition, the low dose required also for 3 and its (S)-(+)-enantiomer, both endowed with efficacious dual α 2C -AR/5-HT 1A -R agonism, confirmed the already reported peculiar relationship between α 2C -AR activation and 5-HT function.…”

“…1,6,7 Therefore, since prolonged abstinence remains a major challenge, strategies addressed to discover multifunctional agents that ameliorate withdrawal symptoms and relieve depressive disorders should be explored. Recently, 8,9 we reported that allyphenyline (1) and cyclomethyline (2) (Chart 1), devoid of sedative side effects, were able at the same low dose (0.05 mg/kg) to significantly decrease the naloxone-precipitated withdrawal syndrome and to exert a …”