Structure-Activity Relationship of the GPR55 Antagonist, CID16020046

Brown, Andrew J.; Castellano-Pellicena, Irene; Haslam, Carl; Nichols, Paula L.; Dowell, Simon J.

doi:10.1159/000493490

Cited by 11 publications

(5 citation statements)

References 35 publications

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“…In this spotlight, LPI-GPR55 axis inhibitors may be an effective strategy to suppress cancer progression. Moreover, a GPR55 peptide ligand was shown to suppress the proliferation of B-lymphoblastoid cell lines [292].…”

Section: Cancermentioning

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: Cancermentioning

confidence: 99%

A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

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“…The pyrazolopyrrolidinone chemotype is well-described in the research and patent literature, with a rich array of reported biological activities, the most prominent of which are p53/MDM2 interaction inhibition (41)(42)(43)(44)(45)(46)(47)(48)(49), phosphodiesterase inhibition (50,51), and GPR55 modulation (52)(53)(54)(55)(56). In addition, there are examples of pyrazolopyrrolidinones exhibiting P2X3 antagonism (57), GPR68 agonism (58), 5-HT1A receptor binding (59), BET inhibition (60, 61), 14-3-3-PMA2 interaction stabilization (62), P-glycoprotein inhibition (63), antitumor activity (64), and antimicrobial activity against various parasitic, viral and bacterial species including T. cruzi (65), HIV (66,67), flaviviruses (68), M. tuberculosis (69, 70), P. falciparum (71,72), and V. cholerae (73).…”

Section: Medicinal Chemistry Of Pyrazolopyrrolidinones Establishing P...mentioning

confidence: 99%

Discovery of pyrazolopyrrolidinones as potent, broad-spectrum inhibitors of Leishmania infection

Kavouris

McCall²,

Giardini³

et al. 2023

Front. Trop. Dis

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IntroductionLeishmaniasis is a parasitic disease that affects more than 1 million people worldwide annually, predominantly in resource-limited settings. The challenge in compound development is to exhibit potent activity against the intracellular stage of the parasite (the stage present in the mammalian host) without harming the infected host cells. We have identified a compound series (pyrazolopyrrolidinones) active against the intracellular parasites of Leishmania donovani and L. major; the causative agents of visceral and cutaneous leishmaniasis in the Old World, respectively.MethodsIn this study, we performed medicinal chemistry on a newly-discovered antileishmanial chemotype, with over 100 analogs tested. Studies included assessments of antileishmanial potency, toxicity towards host cells, and in vitro ADME screening of key drug properties.Results and discussionMembers of the series showed high potency against the deadliest form, visceral leishmaniasis (approximate EC50 ≥ 0.01 µM without harming the host macrophage up to 10.0 µM). In comparison, the most efficient monotherapy treatment for visceral leishmaniasis is amphotericin B, which presents similar activity in the same assay (EC50 = 0.2 µM) while being cytotoxic to the host cell at 5.0 µM. Continued development of this compound series with the Discovery Partnership with Academia (DPAc) program at the GlaxoSmithKline Diseases of the Developing World (GSK DDW) laboratories found that the compounds passed all of GSK’s criteria to be defined as a potential lead drug series for leishmaniasis.ConclusionHere, we describe preliminary structure-activity relationships for antileishmanial pyrazolopyrrolidinones, and our progress towards the identification of candidates for future in vivo assays in models of visceral and cutaneous leishmaniasis.

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“…Interestingly, data shows that CBD acts as an inverse agonist of GPR55 and, therefore, inhibits the LPI-induced stimulation of ERK1/ 2 phosphorylation (Anavi-Goffer et al, 2012) and the stimulation of [ 35 S]GTPγS binding by LPI (Ford et al, 2010). Research has revealed the structure-activity relationship of GPR55 with the selective antagonist CID16020046, while the antagonism of GPR55 has been proposed as an efficacious treatment for several neurological diseases (Brown et al, 2018). CID16020046 has been used to study the physiological role of GPR55 in nociception (Okine et al, 2020), cognitive processes (Marichal-Cancino et al, 2016;Hurst et al, 2017;Marichal-Cancino et al, 2018), and the neuroprotective effects observed in neuroinflammation and Dravet syndrome animal models (Kaplan et al, 2017;Shen et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Intrapallidal injection of cannabidiol or a selective GPR55 antagonist decreases motor asymmetry and improves fine motor skills in hemiparkinsonian rats

et al. 2022

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Cannabidiol (CBD) presents antiparkinsonian properties and neuromodulatory effects, possibly due to the pleiotropic activity caused at multiple molecular targets. Recently, the GPR55 receptor has emerged as a molecular target of CBD. Interestingly, GPR55 mRNA is expressed in the external globus pallidus (GPe) and striatum, hence, it has been suggested that its activity is linked to motor dysfunction in Parkinson’s disease (PD). The present study aimed to evaluate the effect of the intrapallidal injection of both CBD and a selective GPR55 antagonist (CID16020046) on motor asymmetry, fine motor skills, and GAD-67 expression in hemiparkinsonian rats. The hemiparkinsonian animal model applied involved the induction of a lesion in male Wistar rats via the infusion of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle via stereotaxic surgery. After a period of twenty days, a second surgical procedure was performed to implant a guide cannula into the GPe. Seven days later, lysophosphatidylinositol (LPI), CBD, or CID16020046 were injected once a day for three consecutive days (from the 28th to the 30th day post-lesion). Amphetamine-induced turning behavior was evaluated on the 14th and 30th days post-injury. The staircase test and fine motor skills were evaluated as follows: the rats were subject to a ten-day training period prior to the 6-OHDA injury; from the 15th to the 19th days post-lesion, the motor skills alterations were evaluated under basal conditions; and, from the 28th to the 30th day post-lesion, the pharmacological effects of the drugs administered were evaluated. The results obtained show that the administration of LPI or CBD generated lower levels of motor asymmetry in the turning behavior of hemiparkinsonian rats. It was also found that the injection of CBD or CID16020046, but not LPI, in the hemiparkinsonian rats generated significantly superior performance in the staircase test, in terms of the use of the forelimb contralateral to the 6-OHDA-induced lesion, when evaluated from the 28th to the 30th day post-lesion. Similar results were also observed for superior fine motor skills performance for pronation, grasp, and supination. Finally, the immunoreactivity levels were found to decrease for the GAD-67 enzyme in the striatum and the ipsilateral GPe of the rats injected with CBD and CID16020046, in contrast with those lesioned with 6-OHDA. The results obtained suggest that the inhibitory effects of CBD and CID16020046 on GPR55 in the GPe could be related to GABAergic overactivation in hemiparkinsonism, thus opening new perspectives to explain, at a cellular level, the reversal of the motor impairment observed in PD models.

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Structure-Activity Relationship of the GPR55 Antagonist, CID16020046

Cited by 11 publications

References 35 publications

A Guide to Targeting the Endocannabinoid System in Drug Design

A Guide to Targeting the Endocannabinoid System in Drug Design

Discovery of pyrazolopyrrolidinones as potent, broad-spectrum inhibitors of Leishmania infection

Intrapallidal injection of cannabidiol or a selective GPR55 antagonist decreases motor asymmetry and improves fine motor skills in hemiparkinsonian rats

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