Fruitful Adrenergic α2C-Agonism/α2A-Antagonism Combination to Prevent and Contrast Morphine Tolerance and Dependence,

Bello, Fabio Del; Mattioli, Laura; Ghelfi, Francesca; Giannella, Maddalena; Piergentili, Alessandro; Quaglia, Wilma; Cardinaletti, Claudia; Perfumi, Marina; Thomas, Russell J.; Zanelli, Ugo; Marchioro, Carla; Cin, Michele Dal; Pigini, Maria

doi:10.1021/jm100977d

Cited by 31 publications

(49 citation statements)

References 29 publications

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“…These properties are in agreement with those shown by the lead 1 and its enantiomers and confirm that dual α 2C -AR agonism/α 2A -AR antagonism represents a favorable condition for inducing positive effects on morphine dependence. 9 Interestingly, such effects can even be improved by additional 5-HT 1A -R activation. Indeed, unlike clonidine, 1 or the single (S)-(+)-1 enantiomer, 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.…”

Section: (S)-(+)-and (R)-(−)-2-(2-cyclopropylmethyl)propionic Acid Mementioning

confidence: 99%

“…9 The positive effects of 1 on dependence were also displayed by (S)-(+)-1 (potent α 2C -AR full agonist) and (R)-(−)-1 (α 2C -AR partial agonist); they both were endowed with similar α 2A -AR antagonism. 9 To confirm the aforementioned results and discover novel tools for the management of opioid withdrawal symptoms that have a major role in relapse to drug-taking behavior after detoxification, we extended the study to the recently reported allyphenyline analogue 2, 7 now named cyclomethyline, and its enantiomers, prepared in the present investigation. Compound 2 showed interesting α 2C -AR agonism/α 2A -AR antagonism (Table 1), and according to what reported for 1, 7 this functional profile might be associated with a preferred extended molecular conformation.…”

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confidence: 98%

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

Bello

Diamanti

Giannella

et al. 2012

ACS Med. Chem. Lett.

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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.

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Section: (S)-(+)-and (R)-(−)-2-(2-cyclopropylmethyl)propionic Acid Mementioning

confidence: 99%

mentioning

confidence: 98%

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

Bello

Diamanti

Giannella

et al. 2012

ACS Med. Chem. Lett.

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“…In the recent years allyphenyline, a novel α2-AR ligand endowed with peculiar pharmacological profile has been synthetized and characterized [22][23][24]. Among the three α2-AR subtypes allyphenyline behaves as an agonist only at the α2C-AR subtype, while it does not bind to α2B-ARs and behaves as a neutral antagonist at the α2A-AR subtype in vitro [22].…”

Section: Introductionmentioning

confidence: 99%

Dual Alpha2C/5HT1A Receptor Agonist Allyphenyline Induces Gastroprotection and Inhibits Fundic and Colonic Contractility

et al. 2016

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Background. Allyphenyline, a novel α2-adrenoceptor (AR) ligand has been shown to selectively activate α2C-adrenoceptors (AR) and 5HT1A receptors, but also to behave as a neutral antagonist of α2A-ARs. We exploited this unique pharmacological profile to analyze the role of α2C-ARs and 5HT1A receptors in the regulation of gastric mucosal integrity and gastrointestinal motility. Methods. Similar inhibition was observed in the colon, however, in this case only ARC 239 reduced this effect, while neither selective inhibition of α2C-ARs and 5HT1A receptors, nor genetic deletion of α2A-and α2B-ARs influenced it. Conclusions. Activation of both central α2C-ARs and 5HT1A receptors contributes to the gastroprotective action of allyphenyline in rats. Its inhibitory effect on fundic contractions is mediated by 5HT1A receptors, but neither α2-ARs, nor 5HT1A receptors take part in its inhibitory effect on colonic contractility in mice.

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“…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 …”

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confidence: 99%

“…19 On the basis of the interesting results obtained with 1 and 2, the aim of the present study was to widen the availability of tools potentially useful in managing opioid addiction and associated disorders. To this end, we first determined the 5-HT 1A -R profiles of 3 and its enantiomers, 8 and 4−6. 15 The choice of such compounds was suggested by the observation that, analogously to 1 and 2, they were endowed with efficacious α 2C -AR agonism/α 2A -AR antagonism due to their preferred extended conformation.…”

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Exploring Multitarget Interactions to Reduce Opiate Withdrawal Syndrome and Psychiatric Comorbidity

Bello

Diamanti

Giannella

et al. 2013

ACS Med. Chem. Lett.

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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 3 or its (S)-enantiomer and 4, endowed with effective α 2C -AR agonism/α 2A -AR antagonism/5-HT 1A -R agonism, or 7 and 9−11 producing efficacious α 2C -AR agonism/α 2A -AR antagonism/I 2 −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.KEYWORDS: α 2 -Adrenergic ligands, 5-HT 1A agonists, I 2 −IBS ligands, morphine withdrawal symptoms reduction, antidepressant-like effect O pioid exposure is known to induce potent analgesic effect as well as relaxation and euphoria. The repeated use of opiate drugs, both for the relief of chronic or cancer-related pain and for recreational drug-taking behavior, can lead to the development of dependence. Addiction to opioids is a complex syndrome involving tolerance, drug-seeking, and physical dependence with withdrawal avoidance behaviors. It is often characterized as a chronic relapsing condition and is a major health and social issue in most societies. 1 Detoxification, a necessary step for many forms of long-term abstinence-based treatments, makes use of two approaches: tapering using methadone or buprenorphine, or abrupt termination of opioid use, potentially precipitated by an opioid antagonist (i.e., naltrexone) with administration of α 2 -adrenoreceptor (α 2 -AR) agonists to reduce withdrawal symptoms. 1 α 2 -ARs have been demonstrated to be extremely sensitive to opioid exposure. 2 Subdivided into α 2A -, α 2B -, and α 2C -subtypes, α 2 -ARs belong to the superfamily of G-protein-coupled receptors and are widely distributed in the central nervous system (CNS) and in peripheral tissues. 3 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. The α 2C -subtype appears to be involved in feedback inhibition of adrenal cathecolamine release and can contribute to adrenergic-opioid synergy. In the brain, α 2A -and α 2C -ARs, as "heteroreceptors", inhibit dopamine and serotonin release. 3−5 The nonsubtype selective α 2 -AR agonist clonidine has been clinically used alone or in combination with traditional treatments for relief of withdrawal symptoms during detoxification, thus increasing treatment duration. Nevertheless, clonidine, due to its α 2A -AR subtype activation, is responsible for side effects of sedation and hypotension, 1 that limit the use of high doses. Strong association between protracted abstinence and depressive disorder...

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Fruitful Adrenergic α_2C-Agonism/α_2A-Antagonism Combination to Prevent and Contrast Morphine Tolerance and Dependence^,

Cited by 31 publications

References 29 publications

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

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

Dual Alpha2C/5HT1A Receptor Agonist Allyphenyline Induces Gastroprotection and Inhibits Fundic and Colonic Contractility

Exploring Multitarget Interactions to Reduce Opiate Withdrawal Syndrome and Psychiatric Comorbidity

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