The great divide: Separation between in vitro and in vivo effects of PSNCBAM-based CB 1 receptor allosteric modulators

Gamage, Thomas F.; Farquhar, Charlotte E.; Lefever, Timothy W.; Thomas, Brian F.; Nguyễn, Thúy Thị; Zhang, Yanan; Wiley, Jenny L.

doi:10.1016/j.neuropharm.2017.08.008

Cited by 24 publications

(28 citation statements)

References 39 publications

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“…In the same study, the compound was ineffective at attenuating the reduced locomotion, catalepsy, and hypothermia induced by CB 1 agonist Δ 9 -THC. Similar to Org27569, PSNCBAM-1 exhibited a modest but statistically significant reduction in the antinociceptive effects induced by the CB 1 agonist Δ 9 -THC [54]. The above results again revealed the functional selectivity of a CB 1 NAM.…”

Section: Therapeutic Relevance Of Cb 1 Allosteric Modulatorsmentioning

confidence: 58%

“…The initial profile of this compound revealed that PSNCBAM-1 dose-dependently increased the binding of the CB 1 agonist [ 3 [53]. It also inhibited Δ 9 -THC-induced [ 35 S]-GTPγS binding [54]. In yeast reporter assays using the CB 1 receptor, PSNCBAM-1 blocked the agonistic effects of several CB 1 orthosteric agonists, including CP55,940, WIN55,212-2, AEA and 2-AG.…”

Section: Representative Cb 1 Allosteric Modulators and Their Allostermentioning

confidence: 99%

“…Similarly, another allosteric modulator of the CB 1 receptor, PSNCBAM-1, exerted anorectic effects on rats, without any obvious adverse effects on animal behaviors or signs of toxicity under the assessment conditions [46]. However, in a recent study, the anorectic effects of PSNCBAM-1 were not observed in wild-type mice [54]. In the same study, the compound was ineffective at attenuating the reduced locomotion, catalepsy, and hypothermia induced by CB 1 agonist Δ 9 -THC.…”

Section: Therapeutic Relevance Of Cb 1 Allosteric Modulatorsmentioning

confidence: 99%

“…Following the identification of Org27569 and PSNCBAM-1, some functional assays have been employed to characterize the two compounds at molecular, receptor and cellular levels [53,54,[56][57][58][59][60]. The assays employed in the characterization of these compounds include equilibrium binding, CB 1 agonist binding kinetics, CB 1 agonist-induced [ 35 S]GTPγS binding, the G i -mediated inhibition of cAMP production and G s -mediated stimulation of cAMP production, phosphorylation of ERK1/2, and β-arrestin recruitment, cellular hyperpolarization and receptorinternalization and desensitization.…”

Section: Representative Cb 1 Allosteric Modulators and Their Allostermentioning

confidence: 99%

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Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor

Immadi

et al. 2018

Acta Pharmacol Sin

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The cannabinoid type-1 (CB 1) receptor, a G-protein-coupled receptor, is an attractive target for drug discovery due to its involvement in many physiological processes. Historically, drug discovery efforts targeting the CB 1 receptor have focused on the development of orthosteric ligands that interact with the active site to which endogenous cannabinoids bind. Research performed over the last several decades has revealed substantial difficulties in translating CB 1 orthosteric ligands into druggable candidates. The difficulty is mainly due to the adverse effects associated with orthosteric CB 1 ligands. Recent discoveries of allosteric CB 1 modulators provide tremendous opportunities to develop CB 1 ligands with novel mechanisms of action; these ligands may potentially improve the pharmacological effects and enhance drug safety in treating the disorders by regulating the functions of the CB 1 receptor. In this paper, we review and summarize the complex pharmacological profiles of each class of CB 1 allosteric modulators, the development of new classes of CB 1 allosteric modulators and the results from in vivo assessments of their therapeutic value.

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Section: Therapeutic Relevance Of Cb 1 Allosteric Modulatorsmentioning

confidence: 58%

Section: Representative Cb 1 Allosteric Modulators and Their Allostermentioning

confidence: 99%

Section: Therapeutic Relevance Of Cb 1 Allosteric Modulatorsmentioning

confidence: 99%

Section: Representative Cb 1 Allosteric Modulators and Their Allostermentioning

confidence: 99%

See 2 more Smart Citations

Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor

Immadi

et al. 2018

Acta Pharmacol Sin

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“…It further decreased food intake in normal and obese rodents without any adverse side effects [ 424 ]. However, many allosteric ligands so far being described and tested in vitro have not yet shown a sustained effect on CB1 signaling in vivo [ 425 ]. Thus, research still has to put a lot of effort into the successful establishment of allosteric CB1 ligands as potential future pharmacological tools in the clinics.…”

Section: Therapeutic Targeting Of the Ecs In Body Weight Regulatiomentioning

confidence: 99%

Endocannabinoids in Body Weight Control

et al. 2018

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Maintenance of body weight is fundamental to maintain one’s health and to promote longevity. Nevertheless, it appears that the global obesity epidemic is still constantly increasing. Endocannabinoids (eCBs) are lipid messengers that are involved in overall body weight control by interfering with manifold central and peripheral regulatory circuits that orchestrate energy homeostasis. Initially, blocking of eCB signaling by first generation cannabinoid type 1 receptor (CB1) inverse agonists such as rimonabant revealed body weight-reducing effects in laboratory animals and men. Unfortunately, rimonabant also induced severe psychiatric side effects. At this point, it became clear that future cannabinoid research has to decipher more precisely the underlying central and peripheral mechanisms behind eCB-driven control of feeding behavior and whole body energy metabolism. Here, we will summarize the most recent advances in understanding how central eCBs interfere with circuits in the brain that control food intake and energy expenditure. Next, we will focus on how peripheral eCBs affect food digestion, nutrient transformation and energy expenditure by interfering with signaling cascades in the gastrointestinal tract, liver, pancreas, fat depots and endocrine glands. To finally outline the safe future potential of cannabinoids as medicines, our overall goal is to address the molecular, cellular and pharmacological logic behind central and peripheral eCB-mediated body weight control, and to figure out how these precise mechanistic insights are currently transferred into the development of next generation cannabinoid medicines displaying clearly improved safety profiles, such as significantly reduced side effects.

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Endocannabinoid signaling in the central nervous system

Ramirez

Ruiz‐Pérez

Stollenwerk

et al. 2022

Glia

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It is hard to overestimate the influence of the endocannabinoid signaling (ECS) system on central nervous system (CNS) function. In the 40 years since cannabinoids were found to trigger specific cell signaling cascades, studies of the ECS system continue to cause amazement, surprise, and confusion! CB1 cannabinoid receptors are expressed widely in the CNS and regulate cell-cell communication via effects on the release of both neurotransmitters and gliotransmitters. CB2 cannabinoid receptors are difficult to detect in the CNS but seem to "punch above their weight" as compounds targeting these receptors have significant effects on inflammatory state and behavior. Positive and negative allosteric modulators for both receptors have been identified and examined in preclinical studies. Concentrations of the endocannabinoid ligands, N-arachidonoylethanolamine and 2-arachidonoylglycerol (2-AG), are regulated by a combination of enzymatic synthesis and degradation and inhibitors of these processes are available and making their way into clinical trials. Importantly, ECS regulates many essential brain functions, including regulation of reward, anxiety, inflammation, motor control, and cellular development. While the field is on the cusp of preclinical discoveries providing impactful clinical and therapeutic insights into many CNS disorders, there is still much to be learned about this remarkable and versatile modulatory system.

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The great divide: Separation between in vitro and in vivo effects of PSNCBAM-based CB 1 receptor allosteric modulators

Cited by 24 publications

References 39 publications

Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor

Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor

Endocannabinoids in Body Weight Control

Endocannabinoid signaling in the central nervous system

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