Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling

Abstract

Synthetic cannabinoids (SCs) are a class of new psychoactive substances (NPSs) that exhibit high affinity binding to the cannabinoid CB1 and CB2 receptors and display a pharmacological profile similar to the phytocannabinoid (-)-trans-Δ9-tetrahydrocannabinol (THC). SCs are marketed under brand names such as K2 and Spice and are popular drugs of abuse among male teenagers and young adults. Since their introduction in the early 2000s, SCs have grown in number and evolved in structural diversity to evade forensic detection and drug scheduling. In addition to their desirable euphoric and antinociceptive effects, SCs can cause severe toxicity including seizures, respiratory depression, cardiac arrhythmias, stroke and psychosis. Binding of SCs to the CB1 receptor, expressed in the central and peripheral nervous systems, stimulates pertussis toxin-sensitive G proteins (Gi/Go) resulting in the inhibition of adenylyl cyclase, a decreased opening of N-type Ca2+ channels and the activation of G protein-gated inward rectifier (GIRK) channels. This combination of signaling effects dampens neuronal activity in both CNS excitatory and inhibitory pathways by decreasing action potential formation and neurotransmitter release. Despite this knowledge, the relationship between the chemical structure of the SCs and their CB1 receptor-mediated molecular actions is not well understood. In addition, the potency and efficacy of newer SC structural groups has not been determined. To address these limitations, various cell-based assay technologies are being utilized to develop structure versus activity relationships (SAR) for the SCs and to explore the effects of these compounds on noncannabinoid receptor targets. This review focuses on describing and evaluating these assays and summarizes our current knowledge of SC molecular pharmacology.

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

“…CB 1 receptors are mainly located in the central nervous system, thus covering most of the psychoactive effects of SCRAs. Due to the distribution of CB 1 and CB 2 receptors on the terminals of neuron, which mediate a modulation and inhibition of synaptic transmission, cannabinoids have effects on neuronal development, motor function, cognition, and memory, appetite, sleep, thermoregulation, analgesia, reward processes, cardiovascular, respiratory, immune, and reproductive functions [ 7 , 52 , 53 , 54 , 55 ]. Reward, euphoria, memory loss, altered vigilance, anxiety and cognitive deficit, proconvulsant, antinociceptive, cataleptic, hypolocomotion, and hypothermic effects of SCRAs, such as JWH-018, JWH-073, 5F-AMB, 5F-AB-PINACA, and Cumyl-4CN-BINACA, are mediated by CB 1 receptor activation, as demonstrated in CB 1 knock-out mice or by CB 1 -blocking agents [ 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ].…”

“…Interactions of SCRAs has been described with dopamine, serotonin, and glutamate systems, with possible effects on schizophrenia and psychosis after SCRAs intake [ 100 ]. Other non-cannabinoid-mediated interactions include those with other G-coupled protein receptors, capsaicin receptor, and the vanilloid receptor 1 [ 52 , 101 , 102 ]. It should be mentioned that transient receptor potential (TRP) channels might also mediate significant effects of SCRAs, since endogenous endocannabinoids such as anandamide are TRP agonists [ 103 ].…”

WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels

“…Activating CB2 produces antinociception, antiinflammation, and neuroprotection [ 1 ]. In the brain, signaling pathways of activating CB1 and/or CB2 have been revealed involving the phosphorylation of receptors by G protein receptor kinases and subsequently an association with β-arrestin1 or β-arrestin2 resulting in the desensitization and internalization of cannabinoid receptors [ 2 , 12 ]. Besides, activation of CB1 and/or CB2 elicits the dissociation of the βγ subunits (Gi/o(βγ)) of pertussis toxin-sensitive G proteins (Gi/o) from the α subunits (Gi/o(α)) [ 2 , 12 , 13 ].…”

“…Besides, activation of CB1 and/or CB2 elicits the dissociation of the βγ subunits (Gi/o(βγ)) of pertussis toxin-sensitive G proteins (Gi/o) from the α subunits (Gi/o(α)) [ 2 , 12 , 13 ]. Gi/o(α) inhibits adenylyl cyclase, thereby reducing cellular cAMP levels [ 12 ]. Both Gi/o(α) and β-arrestin can also stimulate different members of the mitogen-activated protein kinases family, bringing about additional cellular effects [ 2 , 12 , 13 ].…”

“…Gi/o(α) inhibits adenylyl cyclase, thereby reducing cellular cAMP levels [ 12 ]. Both Gi/o(α) and β-arrestin can also stimulate different members of the mitogen-activated protein kinases family, bringing about additional cellular effects [ 2 , 12 , 13 ]. On the other hand, Gi/o(βγ) modulates the activity of several ion channels.…”