In superior cervical ganglion neurons, N-(piperidiny-1-yl)-5-(4-

The G protein-coupled receptors 3, 6, and 12 (GPR3, GPR6, and GPR12) comprise a family of closely related orphan receptors with no confirmed endogenous ligands. These receptors are constitutively active and capable of signaling through G protein-mediated and non-G protein-mediated mechanisms. These orphan receptors have previously been reported to play important roles in many normal physiological functions and to be involved in a variety of pathological conditions. Although they are orphans, GPR3, GPR6, and GPR12 are phylogenetically most closely related to the cannabinoid receptors. Using β-arrestin2 recruitment and cAMP accumulation assays, we recently found that the nonpsychoactive phytocannabinoid cannabidiol (CBD) is an inverse agonist for GPR3, GPR6, and GPR12. This discovery highlights these orphan receptors as potential new molecular targets for CBD, provides novel mechanisms of action, and suggests new therapeutic uses of CBD for illnesses such as Alzheimer's disease, Parkinson's disease, cancer, and infertility. Furthermore, identification of CBD as a new inverse agonist for GPR3, GPR6, and GPR12 provides the initial chemical scaffolds upon which potent and efficacious agents acting on these receptors can be developed, with the goal of developing chemical tools for studying these orphan receptors and ultimately new therapeutic agents.

No abstract

In this study, the sensitivity of the CB2 receptor to methanethiosulfonate (MTS) derivatives was tested, and a native cysteine residue conferring the sensitivity was identified. By incubating human embryonic kidney 293 cells stably transfected with CB2 receptors and MTS derivatives such as MTS ethylammonium (MTSEA), [ ) for the MTSEA reaction with wild-type CB2 suggests that C2.59(89) resides at the margin of the CB2 binding site crevice. The accessibility of C2.59(89) to MTSEA provides experimental evidence for a possible conformational difference between TMH2 of CB2 versus Rho. Modeling studies undertaken to explore the origin of such differences suggest it is possibly caused by the conformational influence of S2.54(84).

A unique integrated hollow CoP nanospheres embedded carbon nanoarrays has been facilely synthesized from a metal–organic framework precursor, and behaves as a pH-versatile catalyst for both hydrogen evolution and oxygen evolution reactions.

Our data shows that the presence of the polymorphisms at both positions 63 and 316 produce alterations in the CB2 receptor functions. Moreover, these findings strengthen the idea that the CB2 polymorphic receptors may contribute to the etiology of certain diseases.

The data from this study demonstrate that the CB2-selective cannabinoid agonist JWH015 increases aqueous humor outflow facility. The results also indicate that functional CB2 cannabinoid receptors are expressed in trabecular meshwork cells, and these receptors are involved in the enhancement of outflow facility induced by JWH015.

GPR12 is a constitutively active, Gs protein-coupled receptor that currently has no confirmed endogenous ligands. GPR12 may be involved in physiological processes such as maintenance of oocyte meiotic arrest and brain development, as well as pathological conditions such as metastatic cancer. In this study, the potential effects of various classes of cannabinoids on GPR12 were tested using a cAMP accumulation assay. Our data demonstrate that cannabidiol (CBD), a major non-psychoactive phytocannabinoid, acted as an inverse agonist to inhibit cAMP accumulation stimulated by the constitutively active GPR12. Thus, GPR12 is a novel molecular target for CBD. The structure-activity relationship studies of CBD indicate that both the free hydroxyl and the pentyl side chain are crucial for the effects of CBD on GPR12. Furthermore, studies using cholera toxin, which blocks Gs protein and pertussis toxin, which blocks Gi protein, revealed that Gs, but not Gi is involved in the inverse agonism of CBD on GPR12. CBD is a promising novel therapeutic agent for cancer, and GPR12 has been shown to alter viscoelasticity of metastatic cancer cells. Since we have demonstrated that CBD is an inverse agonist for GPR12, this provides novel mechanism of action for CBD, and an initial chemical scaffold upon which highly potent and efficacious agents acting on GPR12 may be developed with the ultimate goal of blocking cancer metastasis.