Metabolic Profiling of CB1 Neutral Antagonists

Seltzman, Herbert H.; Maitra, Rangan; Bortoff, Katharine; Henson, Jay; Reggio, Patricia H.; Wesley, Daniel; Tam, Joseph

doi:10.1016/bs.mie.2017.06.025

Cited by 14 publications

(16 citation statements)

References 34 publications

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“…Other possible strategy is the employment of CB1 neutral antagonists instead of inverse agonists. Such compounds (e.g., PIMSR-10 mg/kg/day) were shown to effectively reduce body weight and adiposity in mice and may be safer in terms of psychiatric adverse effects [221]. Moreover, CB1 NAMs have been proposed as well.…”

Section: Obesitymentioning

confidence: 99%

A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

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The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.

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Section: Obesitymentioning

confidence: 99%

A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

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“…Therefore, it was proposed that neutral CB 1 R antagonists without inverse agonist profiles should retain the therapeutic anti-addictive effects without the unwanted psychiatric effects. Accordingly, several neutral CB 1 R antagonists have been developed, including AM4113, AM6257, NESS0327, LH-21, and PIMSR [37][38][39][40][41]. AM4113 is a pyrazole-3-carboxamide analog of SR141716A [37].…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats

Jordan

Vemuri

et al. 2018

Acta Pharmacol Sin

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Cannabinoid CB receptors (CBRs) have been shown to be a promising target in medication development for the treatment of addiction. However, clinical trials with SR141716A (rimonabant, a selective CBR antagonist/inverse agonist) for the treatment of obesity and smoking cessation failed due to unwanted side effects, such as depression, anxiety, and suicidal tendencies. Recent preclinical studies suggest that the neutral CBR antagonist AM4113 may retain the therapeutic anti-addictive effects of SR141716A in nicotine self-administration models and possibly has fewer unwanted side effects. However, little is known about whether AM4113 is also effective for other drugs of abuse, such as opioids and psychostimulants, and whether it produces depressive side effects similar to SR141716A in experimental animals. In this study, we demonstrated that systemic administration of AM4113 (3 and 10 mg/kg) dose-dependently inhibited the self-administration of intravenous heroin but not cocaine or methamphetamine, whereas SR141716A (3 and 10 mg/kg) dose-dependently inhibited the self-administration of heroin and methamphetamine but not cocaine. In the electrical brain-stimulation reward (BSR) paradigm, SR141716A (3 and 10 mg/kg) dose-dependently increased the BSR stimulation threshold (i.e., decreased the stimulation reward), but AM4113 had no effect on BSR at the same doses, suggesting that SR141716A may produce aversive effects while AM4113 may not. Together, these findings show that neutral CBR antagonists such as AM4113 deserve further research as a new class of CBR-based medications for the treatment of opioid addiction without SR141716A-like aversive effects.

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“…The insights featured in this plan include the recently elucidated 3D crystal structure of the human CB1R (162) and the use of zebrafish as a medium-throughput in vivo screening option due to their eCB/CB1R system's similarity to its human counterpart. The development of CB1R blockers with a neutral antagonist profile (i.e., maintains equilibrium between CB1R activity and inactivity; compare to inverse agonist which shifts CB1Rs to inactive state) could provide distinct safety advantages over inverse agonists such as JD5037 while still preserving efficacy (163). In support of this idea, the CB1R neutral antagonist AM6545 was able to comprehensively restore metabolic function in a mouse model of obesity induced by monosodium glutamate (164).…”

Section: Discussionmentioning

confidence: 99%

Countering the Modern Metabolic Disease Rampage With Ancestral Endocannabinoid System Alignment

et al. 2019

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When primitive vertebrates evolved from ancestral members of the animal kingdom and acquired complex locomotive and neurological toolsets, a constant supply of energy became necessary for their continued survival. To help fulfill this need, the endocannabinoid (eCB) system transformed drastically with the addition of the cannabinoid-1 receptor (CB1R) to its gene repertoire. This established an eCB/CB1R signaling mechanism responsible for governing the whole organism's energy balance, with its activation triggering a shift toward energy intake and storage in the brain and the peripheral organs (i.e., liver and adipose). Although this function was of primal importance for humans during their pre-historic existence as hunter-gatherers, it became expendable following the successive lifestyle shifts of the Agricultural and Industrial Revolutions. Modernization of the world has further increased food availability and decreased energy expenditure, thus shifting the eCB/CB1R system into a state of hyperactive deregulated signaling that contributes to the 21st century metabolic disease pandemic. Studies from the literature supporting this perspective come from a variety of disciplines, including biochemistry, human medicine, evolutionary/comparative biology, anthropology, and developmental biology. Consideration of both biological and cultural evolution justifies the design of improved pharmacological treatments for obesity and Type 2 diabetes (T2D) that focus on peripheral CB1R antagonism. Blockade of peripheral CB1Rs, which universally promote energy conservation across the vertebrate lineage, represents an evolutionary medicine strategy for clinical management of present-day metabolic disorders.

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Metabolic Profiling of CB1 Neutral Antagonists

Cited by 14 publications

References 34 publications

A Guide to Targeting the Endocannabinoid System in Drug Design

A Guide to Targeting the Endocannabinoid System in Drug Design

Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats

Countering the Modern Metabolic Disease Rampage With Ancestral Endocannabinoid System Alignment

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