Understanding Cannabinoid Receptor Modulators

What are cannabinoids?
Cannabinoids, also known as phytocannabinoids, are chemicals in Cannabis that cause drug-like effects in the body, including the central nervous system and the immune system. The main psychoactive cannabinoid in Cannabis is delta-9-THC. Another active cannabinoid is cannabidiol (CBD), which may relieve pain and lower inflammation without causing the "high" of delta-9-THC. Cannabinoids may help treat the side effects of cancer and cancer treatment. Other possible effects of cannabinoids include: Anti-inflammatory activity. Blocking cell growth. Preventing the growth of blood vessels that supply tumors. Antiviral activity. Relieving muscle spasms caused by multiple sclerosis.
What is the endocannabinoid system?
The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the mammalian central nervous system and peripheral nervous system.
Two primary endocannabinoid receptors have been identified: CB1, first cloned in 1990; and CB2, cloned in 1993. CB1 receptors are found predominantly in the brain and nervous system, as well as in peripheral organs and tissues, and are the main molecular target of the endocannabinoid ligand (binding molecule), anandamide, as well as its mimetic phytocannabinoid, THC. One other main endocannabinoid is 2-arachidonoylglycerol (2-AG) which is active at both cannabinoid receptors, along with its own mimetic phytocannabinoid, CBD. 2-AG and CBD are involved in the regulation of appetite, immune system functions and pain management.

Therapeutic strategies aimed at the endocannabinoid system

The endogenous cannabinoid system—named for the plant that led to its discovery—is one of the most important physiologic systems involved in establishing and maintaining human health.
Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. With its complex actions in our immune system, nervous system, and virtually all of the body’s organs, the endocannabinoids are literally a bridge between body and mind. By understanding this system, we begin to see a mechanism that could connect brain activity and states of physical health and disease.

  • The intercellular signaling molecules, their receptors, and synthetic and degradative enzymes from which cannabis gets its powers had been in place for millions of years by the time humans began burning the plants and inhaling the smoke. Despite records going back 4,700 years that document medicinal uses of cannabis, no one knew how it worked until 1964.
  • HC is a lipid, but in 1964, known or suspected neurotransmitters and neuromodulators were water-soluble molecules—peptides, amino acids, or amines—not lipids. Ordinary neuroactive agents interact with cells by binding to specific proteinaceous receptor molecules that are part of the cell surface. Each receptor has an intricate structural pocket into which a particular neurotransmitter fits. The interaction triggers the biochemical and biophysical reactions that affect the physiological properties of the cell.
  • Strong evidence that THC and similar synthetic molecules could bind tightly to specific sites in the brain emerged, implying that THC does indeed work through true receptors. This hypothesis was confirmed in 1990 with the isolation and cloning of the first cannabinoid receptor, CB1,3 and later of CB2.4
  • In the central nervous system (CNS), CB1 is by far the predominant form, although it also exists outside the CNS; CB2 is primarily found outside the CNS, and is associated with the immune system. Both receptor subtypes are 7-transmembrane domain macromolecules of the “G-protein-coupled” class.

CB1 is densely located in the neocortex, hippocampus, basal ganglia, amygdala, striatum, cerebellum, and hypothalamus. These major brain regions mediate a wide variety of high-order behavioral functions, including learning and memory, executive function decision making, sensory and motor responsiveness, and emotional reactions, as well as feeding and other homeostatic processes. Within neuronal circuits, suppression of excitatory transmitter release tends to dampen excitation, while suppression of inhibitory transmitter release favors neuronal network excitation.

Given the enormous complexity of the brain, the endocannabinoid system could affect behavior in an almost limitless number of ways: Simple generalizations of what will happen when CB1 receptors are globally turned on or off are not feasible. The challenge for developers of cannabinoid-based medicines is to find beneficial ways to exploit this powerful yet convoluted feedback system.

Cannabinoid receptors. CB1 and CB2

In the central nervous system (CNS), CB1 is by far the predominant form, although it also exists outside the CNS; CB2 is primarily found outside the CNS, and is associated with the immune system. Both receptor subtypes are 7-transmembrane domain macromolecules of the “G-protein-coupled” class.

CB1 and CB2 must partner with an endogenous ligand, a natural agent for which they would normally act as the proper receptors.

CB2 agonists:

Role of selectivity on in vivo efficacy in a rodent model of analgesia.

Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.

Advances in cannabinoid receptor in neurodegenerative diseases

Since the discovery of cannabinoid receptors and their endogenous ligands in early 1990s, the endocannabinoid system has been shown to play a vital role in several pathophysiological processes. It has been targeted for the treatment of several diseases including neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, Huntington's disease and MS), cancer, obesity, inflammatory bowel disease, neuropathic and inflammatory pain. The last decade has witnessed remarkable advances in the development of cannabinergic ligands displaying high selectivity and potency towards two subtypes of cannabinoid receptors, namely CB1 and CB2.
Recent analysis reveals prolific patenting activity mainly in the CB2 selective agonist area. Limiting the BBB penetrability, thereby, leading to peripherally restricted CB1/CB2 agonists and enhancing CB2-selectivity emerge as likely prerequisites for avoidance of adverse central CB1 mediated side effects.

Argos Medical Sciences is actively analyzing research into the role of selectivity on in vivo efficacy in a rodent model of analgesia