Highly Selective Ligands for Cannabinoid Receptor CB2

University of Pittsburgh researchers have designed and synthesized novel chemical compounds with the ability to selectively bind to the cannabinoid receptor, CB2.

Description

Cannabinoid receptors regulate many biological functions and so are potential target sites in the treatment of various conditions. To date two cannabinoid receptors have been identified; CB1, primarily expressed in the central nervous system (CNS), and CB2, predominantly expressed in the periphery and immune system. CB2 has been shown to mediate bone anabolic action, and selective targeting may provide treatment options for some of the estimated 45 million Americans with poor bone health. Additionally, developing ligands to selectively bind to CB2 receptors may reduce some of the CNS side effects attributed to CB1 binding.

Applications

1. Osteoporosis and bone health
2. Autoimmune diseases
3. Various cancers

Advantages

Medical marijuana (cannabis) is a growing area of research and clinical practice. A limitation to the use of medical marijuana is the binding of cannabinoids to the CB1 receptor, linked to complications of suicide and depression and leading to the withdrawal of some cannabinoid drugs.

These novel compounds bind selectively to CB2 receptors and can potentially provide all the benefits of cannabinoids without the psychotropic side effects caused by CB1 interactions. With a different chemical structure to other cannabinoids in clinical trials, the selective binding to CB2 receptors can result in both agonist and inverse agonist activities, expanding on the ability of these compounds to potentially treat a wide variety of conditions with reduced risk of adverse effects.

Invention Readiness

In vitro testing has shown these compounds are a new class of anti-osteoclast agents. Novel CB2 receptor specific ligands have been designed and synthesized using high-throughput screening, computer-aided drug design, and in-silico modelling. Validation using bioassays resulted in libraries of 41 4-(aminomethyl)-N,N-diethlyanaline compounds being synthesized and undergoing further testing. Seven of these compounds were found to selectively bind to CB2 (selectivity index = 31) with binding affinity <400 nM. An additional compound exhibited selective CB2 inverse agonist affinity (selectivity index = 145) and inhibited osteoclast formation, a process linked to bone degradation and osteoporosis.

IP Status

https://patents.google.com/patent/US11059778B2