Positive allosteric modulation of the cannabinoid type-1 receptor (CB1R) in periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats

Datta, Udita; Kelley, Leslie K.; Middleton, Jason; Gilpin, Nicholas W.

doi:10.1007/s00213-020-05650-5

Cited by 19 publications

(11 citation statements)

References 46 publications

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“…[329][330][331] The use of allosteric modulators of CB 1 R. Examples of CB 1 R allosteric modulators are listed in Table 6 below. -Anti-psychotic -Anti-nociceptive/analgesic in models of neuropathic and/or inflammatory pain [332][333][334][335][336] ii.…”

Section: Cannabinoids Used To Modulate the Ecs In Cannabinoid-researchmentioning

confidence: 99%

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

Lowe

Toyang²,

Steele

et al. 2021

IJMS

162

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The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems. In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development. The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development. The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases. This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.

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Section: Cannabinoids Used To Modulate the Ecs In Cannabinoid-researchmentioning

confidence: 99%

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

Lowe

Toyang²,

Steele

et al. 2021

IJMS

162

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“… The distinct molecular pharmacology of each GAT211 enantiomer demonstrates that the absolute stereochemistry of the benzylic center has a profound effect on ligand engagement and functional activity. , Both GAT228 and GAT229 showed signs of bias for G protein-dependent over β-arrestin2 signaling, as they have two recently profiled ago-PAMs from this laboratory [GAT591 ( 5 ) and GAT593( 6 )] . Both racemic GAT211 and its enantiomers demonstrated preclinical analgesic efficacy and therapeutic activities against glaucoma and Huntington’s disease, all without apparent liabilities (i.e., tolerance, dependence, substance-abuse) associated with conventional CB1R orthosteric agonists. − The enantiospecific allosteric modulation of CB1R by GAT211( 4 ) enantiomers and the attractive in vivo therapeutic profiles of these leads invites expansion of the structure–activity relationship (SAR) around this focused library of 2-phenylindole CB1R activators as detailed herein for optimizing their biological and physicochemical properties and defining the extent to which their pharmacological characteristics are tunable. , In this work, we have exploited the “magic methyl effect” involving tactical replacement of a hydrogen atom by a methyl group in the right place of the molecule, a frequently used strategy for improving potency/efficacy. − …”

Section: Introductionmentioning

confidence: 98%

Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy

et al. 2021

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We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the α-position of nitro group generated two diastereomers, the greater potency and efficacy of erythro, (±)-9 vs threo, (±)-10 constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (±)-9 enantiomers, (−)-(S,R)-13 evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(R,S)-14 was a CB1R allosteric agonist biased toward G protein-vs β-arrestin1/2-dependent signaling. (−)-(S,R)-13 and (+)-(R,S)-14 were devoid of undesirable side effects (triad test), and (+)-(R,S)-14 reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (−)-(S,R)-13 docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-(R,S)-14 preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.

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“…PAG is a midbrain region that is involved in the modulation of nociception, and MORs in the PAG are important targets for analgesia. 91 , 92 , 93 It was reported that the activation of MORs in the ventral PAG could decrease the inhibitory inputs onto the dopamine (DA) neurons in the ventral PAG, the activation of which displayed an antinociceptive effect. 91 Recently, Kandasamy et al.…”

Section: Morsmentioning

confidence: 99%

“… 91 , 92 , 93 It was reported that the activation of MORs in the ventral PAG could decrease the inhibitory inputs onto the dopamine (DA) neurons in the ventral PAG, the activation of which displayed an antinociceptive effect. 91 Recently, Kandasamy et al. found that positive allosteric modulators targeting MORs in the PAG produced antinociception with reduced levels of morphine‐induced side effects such as reward and respiratory depression.…”

Section: Morsmentioning

confidence: 99%

Mechanism of opioid addiction and its intervention therapy: Focusing on the reward circuitry and mu‐opioid receptor

Zhang

Song

Dai

et al. 2022

MedComm

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Opioid abuse and addiction have become a global pandemic, posing tremendous health and social burdens. The rewarding effects and the occurrence of withdrawal symptoms are the two mainstays of opioid addiction. Mu‐opioid receptors (MORs), a member of opioid receptors, play important roles in opioid addiction, mediating both the rewarding effects of opioids and opioid withdrawal syndrome (OWS). The underlying mechanism of MOR‐mediated opioid rewarding effects and withdrawal syndrome is of vital importance to understand the nature of opioid addiction and also provides theoretical basis for targeting MORs to treat drug addiction. In this review, we first briefly introduce the basic concepts of MORs, including their structure, distribution in the nervous system, endogenous ligands, and functional characteristics. We focused on the brain circuitry and molecular mechanism of MORs‐mediated opioid reward and withdrawal. The neuroanatomical and functional elements of the neural circuitry of the reward system underlying opioid addiction were thoroughly discussed, and the roles of MOR within the reward circuitry were also elaborated. Furthermore, we interrogated the roles of MORs in OWS, along with the structural basis and molecular adaptions of MORs‐mediated withdrawal syndrome. Finally, current treatment strategies for opioid addiction targeting MORs were also presented.

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Positive allosteric modulation of the cannabinoid type-1 receptor (CB1R) in periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats

Cited by 19 publications

References 46 publications

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy

Mechanism of opioid addiction and its intervention therapy: Focusing on the reward circuitry and mu‐opioid receptor

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