Development of 3-(4-Chlorophenyl)-1-(phenethyl)urea Analogues as Allosteric Modulators of the Cannabinoid Type-1 Receptor: RTICBM-189 is Brain Penetrant and Attenuates Reinstatement of Cocaine-Seeking Behavior

ABSTRACTContextual drug-associated memories precipitate craving and relapse in cocaine users. Such associative memories can be weakened through interference with memory reconsolidation, a process by which memories are maintained following memory retrieval-induced destabilization. We hypothesized that cocaine-memory reconsolidation requires cannabinoid type 1 receptor (CB1R) signaling based on the fundamental role of the endocannabinoid system in synaptic plasticity and emotional memory processing. Using an instrumental rat model of cocaine relapse, we evaluated whether systemic CB1R antagonism (AM251; 3 mg/kg, I.P.) during memory reconsolidation alters (a) subsequent drug context-induced cocaine-seeking behavior, as well as (b) cellular adaptations and (c) excitatory synaptic physiology in the basolateral amygdala (BLA). Systemic CB1R antagonism – during, but not after, cocaine-memory reconsolidation – reduced drug context-induced cocaine-seeking behavior three days, but not three weeks, later. CB1R antagonism also inhibited memory retrieval-associated increases in BLA zinc finger 268 (zif268) and activity regulated cytoskeletal-associated protein (Arc) immediate-early gene expression and changes in BLA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) subunit phosphorylation that likely contribute to increased receptor membrane trafficking and synaptic plasticity during memory reconsolidation. Furthermore, CB1R antagonism increased memory reconsolidation-associated spontaneous excitatory post-synaptic current frequency in BLA principal neurons during memory reconsolidation. Together, these findings suggest that CB1R signaling modulates cellular and synaptic mechanisms in the BLA during cocaine-memory reconsolidation, thereby facilitating cocaine-memory maintenance. These findings identify the CB1R as a potential therapeutic target for relapse prevention.SIGNIFICANCE STATEMENTDrug relapse can be triggered by the retrieval of context-drug memories upon re-exposure to a drug-associated environment. Context-drug associative memories become destabilized upon retrieval and must be reconsolidated into long-term memory stores in order to persist. Hence, targeted interference with memory reconsolidation can weaken maladaptive context-drug memories and reduce the propensity for drug relapse. Our findings indicate that cannabinoid type 1 receptor (CB1R) signaling is critical for context-cocaine memory reconsolidation and subsequent drug context-induced reinstatement of cocaine-seeking behavior. Furthermore, cocaine-memory reconsolidation is associated with CB1R-dependent immediate-early gene expression and changes in excitatory synaptic proteins and physiology in the basolateral amygdala. Together, our findings provide initial support for CB1R as a potential therapeutic target for relapse prevention.

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Synthesis and Pharmacological Evaluation of 1-Phenyl-3-Thiophenylurea Derivatives as Cannabinoid Type-1 Receptor Allosteric Modulators

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.9b01161 ◽

2019 ◽

Vol 62 (21) ◽

pp. 9806-9823 ◽

Cited By ~ 1

Author(s):

Thuy Nguyen ◽

Thomas F. Gamage ◽

Ann M. Decker ◽

Daniel Barrus ◽

Tiffany L. Langston ◽

...

Keyword(s):

Allosteric Modulators ◽

Cannabinoid Type 1 Receptor ◽

Pharmacological Evaluation

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Rational design of cannabinoid type-1 receptor allosteric modulators: Org27569 and PSNCBAM-1 hybrids

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2021.116215 ◽

2021 ◽

pp. 116215

Author(s):

Thuy Nguyen ◽

Thomas F. Gamage ◽

Ann M. Decker ◽

David B. Finlay ◽

Tiffany L. Langston ◽

...

Keyword(s):

Rational Design ◽

Allosteric Modulators ◽

Cannabinoid Type 1 Receptor

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Basolateral amygdala CB1 receptors modulate HPA axis activation and context-cocaine memory strength during reconsolidation

10.1101/2020.07.18.209932 ◽

2020 ◽

Author(s):

Jessica A. Higginbotham ◽

Nicole M. Jones ◽

Rong Wang ◽

Ryan J. McLaughlin ◽

Rita A. Fuchs

Keyword(s):

Memory Retrieval ◽

Basolateral Amygdala ◽

Memory Reconsolidation ◽

Long Term Memory ◽

Memory Strength ◽

Corticosterone Concentration ◽

Cannabinoid Type 1 Receptor ◽

Cocaine Seeking ◽

Seeking Behavior ◽

The Impact

ABSTRACTRe-exposure to a cocaine-associated context triggers craving and relapse through the retrieval of salient context-drug memories. Upon retrieval, context-drug memories become labile and temporarily sensitive to modification before they are reconsolidated into long-term memory stores. Cannabinoid type 1 receptor (CB1R) signaling is necessary for cocaine-memory reconsolidation and associated glutamatergic plasticity in the basolateral amygdala (BLA); however, it remains unclear whether CB1Rs in the BLA mediate this phenomenon. To investigate this question, we examined whether CB1R antagonist or agonist administration into the BLA immediately after cocaine-memory retrieval (i.e., during memory reconsolidation) alters cocaine-memory strength and subsequent drug context-induced cocaine-seeking behavior in an instrumental rodent model of cocaine relapse. Intra-BLA administration of the CB1R antagonist, AM251 (0.3 µg/hemisphere) – during, but not after, memory reconsolidation – increased drug context-induced cocaine-seeking behavior three days later, while the CB1R agonist, WIN55,212-2 (0.5 µg/hemisphere) failed to alter this behavior. Furthermore, AM251 administration into the posterior caudate putamen (anatomical control region) during memory reconsolidation did not alter subsequent context-induced cocaine-seeking behavior. In a follow-up experiment, cocaine-memory retrieval elicited robust hypothalamic-pituitary-adrenal axis activation, as indicated by an increase in blood serum corticosterone concentration, and this response was selectively extended by intra-BLA AM251 administration during the putative time of memory reconsolidation relative to all control conditions. Together, these findings suggest that CB1R populations in the BLA gate memory strength or interfere with memory maintenance, possibly by diminishing the impact of cue-induced arousal on the integrity of the reconsolidating memory trace or on the efficiency of the memory reconsolidation process.

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Faculty Opinions recommendation of Differential control over cocaine-seeking behavior by nucleus accumbens core and shell.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1018246.206702 ◽

2004 ◽

Author(s):

Eric Nestler

Keyword(s):

Nucleus Accumbens ◽

Nucleus Accumbens Core ◽

Cocaine Seeking ◽

Seeking Behavior ◽

Differential Control ◽

Accumbens Core

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Faculty Opinions recommendation of Disrupting reconsolidation of drug memories reduces cocaine-seeking behavior.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1028296.337165 ◽

2005 ◽

Author(s):

Kent Berridge

Keyword(s):

Cocaine Seeking ◽

Seeking Behavior

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Dopaminylation in Psychostimulant use Disorder Protects Against Psychostimulant Seeking Behavior by Normalizing Nucleus Accumbens (NAc) Dopamine Expression

Current Psychopharmacologye ◽

10.2174/2211556009666210108112737 ◽

2021 ◽

Vol 09 ◽

Author(s):

Kenneth Blum ◽

Mark S Gold ◽

Jean L. Cadet ◽

David Baron ◽

Abdalla Bowirrat ◽

...

Keyword(s):

Nucleus Accumbens ◽

Histone H3 ◽

D2 Receptor ◽

Reward Processing ◽

Allelic Polymorphism ◽

Cocaine Withdrawal ◽

Src Signaling ◽

Chronic Cocaine ◽

Cocaine Seeking ◽

Seeking Behavior

Background: Repeated cocaine administration changes histone acetylation and methylation on Lys residues and Deoxyribonucleic acid (DNA) within the nucleus accumbens (NAc). Recently Nestler’s group explored histone Arg (R) methylation in reward processing models. Damez-Werno et al. (2016) reported that during investigator and selfadministration experiments, the histone mark protein-R-methyltransferase-6 (PRMT6) and asymmetric dimethylation of R2 on histone H3 (H3R2me2a) decreased in the rodent and cocaine-dependent human NAc. Overexpression of PRMT6 in D2-MSNs in all NAc neurons increased cocaine seeking, whereas PRMT6 overexpression in D1-MSNs protects against cocaine-seeking. Hypothesis: Hypothesizing that dopaminylation (H3R2me2a binding) occurs in psychostimulant use disorder (PSU), and the binding inhibitor Srcin1, like the major DRD2 A2 allelic polymorphism, protects against psychostimulant seeking behavior by normalizing nucleus accumbens (NAc) dopamine expression. Discussion: Numerous publications confirmed the association between the DRD2 Taq A1 allele (30-40 lower D2 receptor numbers) and severe cocaine dependence. Lepack et al. (2020) found that acute cocaine increases dopamine in NAc synapses, results in histone H3 glutamine 5 dopaminylation (H3Q5dop), and consequent inhibition of D2 expression. The inhibition increases with chronic cocaine use and accompanies cocaine withdrawal. They also found that the Src kinase sig-naling inhibitor 1 (Srcin1 or p140CAP) during cocaine withdrawal reduced H3R2me2a binding. Consequently, this inhibited dopaminylation induced a “homeostatic brake.” Conclusion: The decrease in Src signaling in NAc D2-MSNs, like the DRD2 Taq A2 allele, a well-known genetic mechanism protective against SUD normalized nucleus accumbens (NAc) dopamine expression and decreased cocaine reward and motivation to self-administer cocaine. The Srcin1 may be an important therapeutic target.

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Molecular Docking and Molecular Dynamics Simulation Studies of Triterpenes from Vernonia patula with the Cannabinoid Type 1 Receptor

International Journal of Molecular Sciences ◽

10.3390/ijms22073595 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3595

Author(s):

Md Afjalus Afjalus Siraj ◽

Md. Sajjadur Rahman ◽

Ghee T. Tan ◽

Veronique Seidel

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Binding Affinity ◽

Docking Studies ◽

Dynamics Simulation ◽

Simulation Studies ◽

Cannabinoid Type 1 Receptor ◽

Docking Approach

A molecular docking approach was employed to evaluate the binding affinity of six triterpenes, namely epifriedelanol, friedelin, α-amyrin, α-amyrin acetate, β-amyrin acetate, and bauerenyl acetate, towards the cannabinoid type 1 receptor (CB1). Molecular docking studies showed that friedelin, α-amyrin, and epifriedelanol had the strongest binding affinity towards CB1. Molecular dynamics simulation studies revealed that friedelin and α-amyrin engaged in stable non-bonding interactions by binding to a pocket close to the active site on the surface of the CB1 target protein. The studied triterpenes showed a good capacity to penetrate the blood–brain barrier. These results help to provide some evidence to justify, at least in part, the previously reported antinociceptive and sedative properties of Vernonia patula.

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