大麻Ⅰ型受体抑制剂研究进展

临床试验表明,大麻Ⅰ型受体(CB1)抑制剂利莫那班(rimonabant)在治疗肥胖和戒烟方面具有良好效果[1],CB1受体抑制剂还具有治疗药物成瘾、认知和记忆紊乱、神经错乱等疾病的潜力。CB1受体抑制剂与诸多疾病的相关性大大推进了新的CB1受体抑制剂的发展。本文主要对各种CB1受体抑制剂的结构及活性研究的最新进展进行综述。     

Recent advances in CB1 cannabinoid receptor antagonists

Cannabinoid CB1 receptor antagonists are currently the subject of intensive research due to their highly promising therapeutic prospects. Novel chemical entities having CB1 antagonistic properties have recently been disclosed by several pharmaceutical companies and some academic research groups, some of which are close structural analogs of the leading compound rimonabant (SR-141716A; Sanofi-Synthélabo). A considerable number of these CB1 antagonists are bioisosteres that are derived from rimonabant by the replacement of the pyrazole moiety with an alternative heterocycle. As well as these achiral compounds, Solvay Pharmaceuticals have disclosed a novel class of chiral pyrazolines that are potent and CB1/CB2 subtype-selective cannabinoid receptor antagonists, in which the interactions with the CB1 receptor are highly stereoselective.     

Syntheses of two isotopically labeled CB1 receptor antagonists

Synthesis of deuterium‐labeled CB₁ receptor antagonist 2‐d₉ was accomplished in three steps by alkylation of 2‐nitrophenylacetonitrile with cyclopentyl‐d₉ bromide, reductive cyclization of the resulting secondary nitrile into the 3‐cyclopentyl indole‐d₉ and its N‐sulfonylation with corresponding p‐amidosulfonyl chloride. Another, structurally related, CB₁ receptor antagonist 1 was radiolabeled with carbon‐14 by oxidative cleavage of 3‐cyclopentyl indole followed by the ring closure of o‐acyl substituted N‐formylaniline with potassium cyanide‐[¹⁴C], in situ reduction‐elimination of the intermediate amino alcohol, and N‐sulfonylation of the resulting 3‐cyclopentyl indole‐2‐[¹⁴C].     

Clonidine and opiate receptor antagonists in the treatment of heroin addiction

Good results in detoxification methods have been reached using both together clonidine and opiate receptors antagonists. One hundred fifty-two heroin-abusing patients were studied evaluating withdrawal symptoms after therapy with (a) clonidine only, (b) clonidine and naltrexone, (c) clonidine and naloxone, and (d) placebos. Treatment results, emotional and behavioral changes, and involvement in psychosocial programs were evaluated after a 6-month follow-up. Although opiate antagonists were able to induce slight and transient withdrawal signs and symptoms, there was, in the group of patients treated with clonidine and naltrexone together, a low percentage of catabolites in urine and an improvement in mood and family relationships. Furthermore, the patients that underwent longer naltrexone treatment showed a stronger involvement in psychosocial programs, and even their relatives demonstrated more interest in the recovery program. A decrease in the difficulties of accepting an opiate antagonists treatment and a different evaluation of withdrawal syndrome were the results of an early use of naltrexone.     

Pharmacogenetics and nicotine addiction treatment

This review focuses on the current status of, and future directions for, pharmacogenetic research on nicotine dependence and smoking cessation treatment. Pharmacological treatment involving nicotine replacement therapy and bupropion for nicotine addiction and smoking cessation has been shown to be efficacious when provided in combination with behavioral support. Cessation rates remain somewhat modest, however, and one possibility is that success rates may be enhanced by offering treatments tailored to an individual's genotype. Nonetheless, research on this issue remains in its infancy, and although the scope for individualized treatment tailored to genotype is promising, there are substantial practical, ethical and social considerations that must be addressed before such research is translated into clinical practice.     

Cannabinoid-1 receptor (CB1R) blockers as medicines: beyond obesity and cardiometabolic disorders to substance abuse/drug addiction with CB1R neutral antagonists

INTRODUCTION: Addiction to chemical substances with abuse potential presents medical needs largely unsolved by extant therapeutic strategies. Signal transmission through the cannabinoid-1 receptor (CB1R) in the central nervous system (CNS) modulates neurotransmitters/neuronal pathways contributing to the rewarding properties and hedonic effects of certain nondrug stimuli (e.g., food) and many prototypical addictive drugs, promoting excessive intake and its pathological consequences. Typical CB1R antagonists/inverse agonists reduce the rewarding effects and normalize behavioral phenotypes associated with food and abused drugs, but carry an unacceptable adverse-event profile that may reflect, at least partly, their intrinsic ability to alter basal homeostatic CB1R signaling in the CNS and elicit a negative efficacy response. Alternatively, peripherally biased CB1R inverse agonists with limited CNS permeability and putative CB1R neutral antagonists expressing modest (if any) inverse-agonist efficacy are garnering attention for treating obesity and related cardiometabolic complications with a potentially enhanced benefit-to-risk profile. AREAS COVERED: This mini-review calls attention to the proposition that CB1R neutral antagonists offer attractive opportunities for pharmacotherapeutic exploitation in the substance abuse/drug addiction space, whereas the restricted CNS accessibility of peripherally biased CB1R inverse agonists circumscribes their therapeutic utility for this indication. EXPERT OPINION: The unique preclinical pharmacology, efficacy profiles, and reduced adverse-event risk of CB1R neutral antagonists make them worthy of translational study for their potential therapeutic application beyond obesity/cardiometabolic disease to include substance-abuse/drug-addiction disorders.     

Cannabinoid-1 receptor (CB1R) blockers as medicines: beyond obesity and cardiometabolic disorders to substance abuse/drug addiction with CB1R neutral antagonists

Introduction : Addiction to chemical substances with abuse potential presents medical needs largely unsolved by extant therapeutic strategies. Signal transmission through the cannabinoid-1 receptor (CB1R) in the central nervous system (CNS) modulates neurotransmitters/neuronal pathways contributing to the rewarding properties and hedonic effects of certain nondrug stimuli (e.g., food) and many prototypical addictive drugs, promoting excessive intake and its pathological consequences. Typical CB1R antagonists/inverse agonists reduce the rewarding effects and normalize behavioral phenotypes associated with food and abused drugs, but carry an unacceptable adverse-event profile that may reflect, at least partly, their intrinsic ability to alter basal homeostatic CB1R signaling in the CNS and elicit a negative efficacy response. Alternatively, peripherally biased CB1R inverse agonists with limited CNS permeability and putative CB1R neutral antagonists expressing modest (if any) inverse-agonist efficacy are garnering attention for treating obesity and related cardiometabolic complications with a potentially enhanced benefit-to-risk profile.

Areas covered : This mini-review calls attention to the proposition that CB1R neutral antagonists offer attractive opportunities for pharmacotherapeutic exploitation in the substance abuse/drug addiction space, whereas the restricted CNS accessibility of peripherally biased CB1R inverse agonists circumscribes their therapeutic utility for this indication.

Expert opinion : The unique preclinical pharmacology, efficacy profiles, and reduced adverse-event risk of CB1R neutral antagonists make them worthy of translational study for their potential therapeutic application beyond obesity/cardiometabolic disease to include substance-abuse/drug-addiction disorders.     

A therapeutic role for cannabinoid CB1 receptor antagonists in major depressive disorders

Cannabinoid receptors in the CNS have been implicated in the control of appetite, cognition, mood and drug dependence. Recent findings support the hypothesis that cannabinoid CB1 receptor blockade might be associated with antidepressant and anti-stress effects. A novel potential antidepressant drug class based on this mechanism is supported by the neuroanatomical localization of CB1 receptors and signal transduction pathways that are involved in emotional responses, together with the antidepressant-like neurochemical and behavioral effects induced by CB1 receptor antagonists. Selective CB1 receptor antagonists are in development for the treatment of obesity and tobacco smoking, and could be tested for antidepressant efficacy because recent results of clinical studies suggest that they would also treat comorbid symptoms of depression such as cognitive deficiencies, weight gain, impulsivity and dependence disorders. Thus, CB1 receptor antagonism might constitute an integrated pharmacotherapeutic approach that impacts the affective, cognitive, appetitive and motivational neuronal networks involved in mood disorders.     

Cannabinoid CB1 receptor antagonist rimonabant disrupts nicotine reward-associated memory in rats

Exposure to cues previously associated with drug intake leads to relapse by activating previously acquired memories. Based on previous findings, in which cannabinoid CB₁ receptors were found to be critically involved in specific aspects of learning and memory, we investigated the role of CB₁ receptors in nicotine reward memory using a rat conditioned place preference (CPP) model. In Experiment 1, rats were trained for CPP with alternating injections of nicotine (0.5 mg/kg, s.c.) and saline to acquire the nicotine-conditioned memory. To examine the effects of rimonabant on the reconsolidation of nicotine reward memory, rats were administered rimonabant (0, 0.3, and 3.0 mg/kg, i.p.) immediately after reexposure to the drug-paired context. In Experiment 2, rats were trained for CPP similarly to Experiment 1. To examine the effects of rimonabant on the reinstatement of nicotine reward memory, rimonabant (0, 0.3, and 3.0 mg/kg, i.p.) was administered before the test of nicotine-induced CPP reinstatement. In Experiment 3, to evaluate whether rimonabant itself produces a reward memory, rats were trained for CPP with alternating injections of different doses of rimonabant (0, 0.3, and 3.0 mg/kg) and saline. Rimonabant at a dose of 3.0 mg/kg significantly disrupted the reconsolidation of nicotine memory and significantly blocked the reinstatement of nicotine-induced CPP. However, rimonabant itself did not produce CPP. These findings provide clear evidence that CB₁ receptors play a role in nicotine reward memory, suggesting that CB₁ receptor antagonists may be a potential target for managing nicotine addiction.     

Investigational sigma-1 receptor antagonists for the treatment of pain

Introduction: The sigma-1 receptor (σ₁R) is a ligand-regulated molecular chaperone that interacts with other proteins, including NMDA and opioid receptors, to modulate their activity. Convergent evidence indicates that σ₁R antagonists exert inhibitory effects (and agonists stimulatory effects) on pain by stepping down the intracellular signaling cascades involved in transduction of noxious stimuli and plastic changes (i.e., sensitization phenomena) associated with chronic pain states.

Areas covered: This review addresses three primary domains. The first focuses on mechanisms underlying the antinociceptive effects of σ₁R antagonists. The second addresses evidence gained using pharmacological tools and experimental drugs in the discovery phase and clinical development. Finally, the article outlines the potential benefits of σ₁R antagonists, alone or in combination, in the context of available pain therapeutics.

Expert opinion: There is a critical need for new analgesics based on new mechanisms of action. Target identification requires convincing evidence relating targets to function. In turn, target validation requires confirmation of therapeutic benefits, ideally in humans. Current preclinical evidence provides strong rationale for σ₁R antagonists in pain. The outcome of clinical studies with the most advanced investigational σ₁R antagonist, S1RA (E-52862), will be of great interest to ascertain the potential of this new therapeutic approach to pain management.     

Alterations in behavioral flexibility by cannabinoid CB1 receptor agonists and antagonists

Rationale Cannabinoid CB₁ receptors are expressed in the prefrontal cortex, but their role in mediating executive functions such as behavioral flexibility is unclear.Objective The present study examined the effect of pharmacological activation or blockade of the cannabinoid CB₁ receptors on behavioral flexibility using a strategy set-shifting task conducted on a cross maze.Materials and methods In experiment 1, rats initially were trained to turn left or right while ignoring the visual cue to obtain a food; on the second test day, rats had to inhibit the previously learned rule and approach the cue to obtain the food. In experiment 2, the order of discrimination training was reversed.Results Administration of the cannabinoid CB₁ receptor agonist HU-210 before the set-shift on day 2 elicited dose-dependent effects on performance. A 20-μg/kg dose of HU-210 increased perseverative errors, whereas the effects of a lower, 5-μg/kg dose caused differential effects depending on whether rats were required to shift from a response to a visual-cue discrimination strategy or vice versa. Conversely, administration of a 2-mg/kg, but not a 5-mg/kg dose of the CB₁ receptor antagonist AM251 reduced perseverative errors.Conclusions These data demonstrate a biphasic and dose-sensitive role for the cannabinoid system in behavioral flexibility, which in turn may have clinical implications for the role of the endocannabinoid system in psychiatric disorders where behavioral flexibility is compromised.     

Keynote review: Medicinal chemistry strategies to CB1 cannabinoid receptor antagonists

The proven clinical efficacy of the CB(1) cannabinoid receptor antagonist rimonabant in both obesity and smoking cessation and its therapeutic potential in other disorders has given a tremendous impetus to the discovery of novel CB(1) antagonists. The number of disclosed patents wherein novel chemical entities having CB(1) antagonistic or inverse agonistic properties have been claimed has exploded. Besides novel compound classes that were identified in screening, rational medicinal chemistry approaches such as conformational constraint and scaffold hopping have been successfully applied. CB(1) receptor modelling has provided insight into crucial receptor-ligand interaction points thereby leading to a general CB(1) inverse agonist pharmacophore model.     

CRH-sub-1 receptor antagonists for the treatment of depression and anxiety

From basic and clinical studies, ample evidence has emerged that abnormalities of stress hormone regulation observed in depression and anxiety are caused by elevated secretion of hypothalamic corticotropin-releasing hormone (CRH). This neuropeptide acts through CRH1 receptors to produce a number of anxiety- and depression-like symptoms, which has resulted in extensive validation of CRH1 receptors as a potential drug target. A number of orally available nonpeptidergic small molecules that are able to pass the blood-brain barrier have been discovered. Some of these compounds have entered clinical development. The authors summarize results from clinical studies of 2 CRH1 antagonists. One study designed as a safety and tolerability study also monitored amelioration of depression under 2 dose-escalation regimens. The compound studied, NBI-30775/R121919, was found to have a clinical profile comparable to that of paroxetine. In a second study the effect of another CRH1 antagonist, NBI-34041, on stress hormone secretion in response to a psychosocial stressor was investigated. Administration of this compound to healthy controls was found to reduce the stress-elicited secretion of stress hormones. However, neither compound impaired the CRH-induced release of adrenocorticotropic hormone and cortisol, rejecting the possibility that the stress hormone system is impaired by CRH1 antagonists. From these studies the authors conclude that both CRH1 antagonists have psychotropic effects unrelated to their neuroendocrine action, in line with behavioral data obtained from transgenic mice with CRH1 gene deletions. The psychotropic effects observed in the clinical studies underscore that CRH1 antagonists constitute a novel treatment of depression and anxiety but may also serve to prevent negative sequelae of severe stressors.     

Current evidence supporting a role of cannabinoid CB1 receptor (CB1R) antagonists as potential pharmacotherapies for drug abuse disorders

Since the discovery of the cannabinoid CB1 receptor (CB1R) in 1988, and subsequently of the CB2 receptor (CB2R) in 1993, there has been an exponential growth of research investigating the functions of the endocannabinoid system. The roles of CB1Rs have been of particular interest to behavioral pharmacologists because of their selective presence within the central nervous system (CNS) and because of their association with brain-reward circuits involving mesocorticolimbic dopamine systems. One potential role that has become of considerable recent focus is the ability of CB1Rs to modulate the effects of drugs of abuse. Many drugs of abuse elevate dopamine levels, and the ability of CB1R antagonists or inverse agonists to attenuate these elevations has suggested their potential application as pharmacotherapies for treating drug abuse disorders. With the identification of the selective CB1R antagonist, SR141716, in 1994, and its subsequent widespread availability, there has been a rapid expansion of research investigating its ability to modulate the effects of drugs of abuse. The preliminary clinical reports of its success in retarding relapse in tobacco users have accelerated this expansion. This report critically reviews preclinical and clinical studies involving the ability of CB1R antagonists to attenuate the effects of drugs of abuse, while providing an overview of the neuroanatomical and neurochemical points of contact between the endocannabinoid system and systems mediating abuse-related effects.     

NK1 receptor antagonists under investigation for the treatment of affective disorders

Substance P-neurokinin-1 (NK1) receptor pathways have been repeatedly implicated in the pathophysiology of affective disorders. Anatomical studies in humans have shown a high expression of NK1 receptors in brain regions that are important for the regulation of affective behaviours and stress responses. A large body of evidence that has been generated from animal experiments indicates that treatment with a selective NK1 receptor antagonist might be effective in the treatment of certain forms of anxiety and depressive disorders. Accordingly, numerous NK1 receptor antagonists have either been synthesised and are under clinical development, or have already been tested in clinical trials. However, the initial encouraging clinical results were followed by repeated demonstrations of a lack of effectiveness, thus disappointment and doubt currently surrounds the idea that these compounds may become effective antidepressants. Research continues and novel molecules may show better pharmacokinetic and pharmacodynamic properties and, therefore, may achieve therapeutic success. Furthermore, NK1 receptor antagonists that are ineffective in the treatment of mood disorders may still prove to be effective in the treatment of anxiety problems.