Exploring Multitarget Interactions to Reduce Opiate Withdrawal Syndrome and Psychiatric Comorbidity

Abstract

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...

Combined Interactions with I1-, I2-Imidazoline Binding Sites and α2-Adrenoceptors To Manage Opioid Addiction

“…In particular, the combined I 1 -/I 2 -IBS/α 2 -ARs interaction appeared more favorable, as demonstrated by the higher efficacy displayed by 9 both in contrasting and preventing morphine withdrawal. Moreover, such a combination also appeared more favorable than that produced by 2 (I 2 -IBS/α 2 -ARs), already evaluated in the same assays 18 (see Table S2). Therefore, 9 might be considered a promising tool useful in managing opioid addiction, potentially lacking in sedative and hypotensive side effects, due to its α 2A -AR antagonist profile.…”

A Novel Class of Dopamine D4 Receptor Ligands Bearing an Imidazoline Nucleus

“…3 Using this molecular core, over many years we have developed several ligands directed to different biological systems including α 2 -adrenergic and 5-HT 1A -serotoninergic receptors and imidazoline binding sites (I-IBS). Some of these compounds showed interesting in vivo pharmacological properties such as antidepressant 4 and antinociceptive 5 activities, enhancement of morphine-induced analgesia, 6 decrease of both acquisition and expression of morphine tolerance and dependence, 7 as well as hyperanxiety-like behavior after alcohol intoxication, 8 hypotensive and bradicardic effects. 9 …”

The Versatile 2‐Substituted Imidazoline Nucleus as a Structural Motif of Ligands Directed to the Serotonin 5‐HT1A Receptor

“…Our experience also highlighted that the bridge (X) and the aromatic area (Ar) forming the substituent in the 2‐position of the imidazoline nucleus display different functions. Indeed, minor chemical modification of the bridge determines preferential or multitarget recognition, whereas modification in the aromatic region is generally responsible for the functional behavior of the ligand …”

“…Interestingly, the beneficial effects of 1 as well as 2 and 3 on morphine dependence proved to be associated, at the same low dose, to a significant antidepressant effect. Experiments performed in the presence of the α 2 ‐AR antagonist yohimbine and the serotonin 5‐HT 1A receptor (5‐HT 1A ‐R) antagonist WAY100135 suggested that not only α 2C ‐AR but also 5‐HT 1A ‐R activation was involved in the observed antidepressant‐like activity . In addition, 1 reduced hyperanxiety‐like behavior after alcohol intoxication at the same low dose .…”

“…This effect was clearly mediated by 5-HT 1A ,a si tw as significantly reduced by pretreatment with the 5-HT 1A antagonist WAY100635. minor chemical modificationo ft he bridge determines preferential or multitarget recognition, [4,5] whereas modification in the aromatic region is generally responsible for the functional behavior of the ligand. [6,7] Among the most interesting synthesized compounds, the a 2C -AR agonist/a 2A -AR antagonist allyphenyline (1) [7] proved to be able to enhance morphine analgesia (owing to its a 2C -AR agonism) at the low dose of 0.05 mg kg À1 ,p reventing and reversing morphinet olerance andd ependence withouts edative side effects (owing to its a 2A -AR antagonism).…”