Functional selectivity in cannabinoid signaling.
Cannabinoid (CB) agonists exhibit numerous potentially useful pharmacological properties, but unwanted side effects limit their use in clinical practice. Thus, novel strategies are needed to identify potential CB pharmaceuticals with fewer side effects. Activated CB receptors initiate multiple parallel intracellular signal transduction cascades. In the present paper we will review experimental data indicating that structurally different classes of CB agonists may exhibit selectivity toward individual subsets of intracellular signaling pathways. In support of this, recent findings indicate that chemically distinct classes of CB agonists frequently differ in their rank order of potency to produce analgesia versus other central nervous system effects in vivo. Structurally different agonists were also found to differ in their abilities to activate individual G protein types in vitro. Since it was suggested earlier that structurally distinct CB agonists may interact differently with the CB receptors, it has been hypothesized that different classes of cannabinoid agonists may stabilize unique active CB receptor conformations, leading to functional selectivity in CB receptor signaling. In order to obtain a direct proof for this hypothesis, we recently employed a highly sensitive biophysical method, plasmon-waveguide resonance (PWR) spectroscopy. PWR experiments have provided a direct proof that structurally different CB agonists produce qualitatively distinct changes in the shape and/or membrane orientation of the CB1 receptors, leading to functional selectivity in G protein activation. We expect that by identification of CB agonists that selectively activate preferred intracellular signaling pathways novel pharmacological lead structures can be identified for the design of improved CB analgesics with fewer side effects.
Varga
E V
EV
University of Arizona, College of Medicine, Department of Pharmacology, Tucson, AZ 85724, USA. evarga@email.arizona.edu
Georgieva
T
T
Tumati
S
S
Alves
I
I
Salamon
Z
Z
Tollin
G
G
Yamamura
H I
HI
Roeske
W R
WR
D063386:Cannabinoid Receptor Agonists; D002490:Central Nervous System / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D056747:Immunomodulation / Q000187:drug effects; D007473:Ion Channels / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction
D063386:Cannabinoid Receptor Agonists; D007473:Ion Channels; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases