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The effect of synthetic cannabinoids on the human body

Brain

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The development of addiction to synthetic psychoactive substances is a relevant social issue in most countries in the world, which has now acquired national importance. This issue requires global attention, firstly, due to the rapid growth in the number of people involved in the use of psychoactive substances, and secondly, due to the consequences of antisocial behavior of these people: crime commitment, development of various diseases caused by psychoactive substance abuse.

One of these psychoactive substances is smoking herbal mixture — "spice". It is available on the market in form of herbs with a chemical applied, and it has rapidly gained popularity among young people.
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Classification of substances that are part of smoking mixtures:

1. Classical cannabinoids-ocannabinol, other chemical compounds present in cannabis, and structurally related synthetic analogues, for example, AM-411, AM-906, HU-210, O-1184;
2. Non-classical cannabinoids-cyclohexylphenols or 3-arylcyclohexanols, for example, CP-55,244, CP-55,940, CP-47,497 (and homologues of C6-9);
3. Hybrid cannabinoids-combinations of structural features of classical and non-classical cannabinoids, for example, AM-4030;
4. Eicosanoids — endocannabinoids such as anandamide (AEA) and their synthetic analogues, for example, methanandamide (AM-356);
5. Other. They include other structural types - diarylpyrazoles (for example, Rimonabant), naphthoylpyrroles (for example, JWH-307), naphthylmethylindenes (for example, JWH-176) and indazolcarboxamides (for example, APINACA).
6. Aminoalkylindoles, which can be further divided into the following groups:
* phenylacetylindoles (JWH-250, JWH-251);
* benzoylindoles (pravadolin, AM-694, RSC-4);
* naphthylmethylindoles (JWH-184);
* cyclopropoyl-idols (UR-144, XLR-11);
* adamantoilindoles (AB-001, AM-1248);
* Indole carboxamides (APICA, STS-135);
* naphthoylindoles (for example, JWH-015, JWH-018, JWH-073, JWH-081, JWH-122, JWH-200, JWH-210, JWH-398);

Many derivatives and analogues of the compound classes mentioned above can be synthesized by halogen, alkyl, alkoxyl or other substituents binding to one of the aromatic cyclic systems.

The effect of classical cannabinoids.
To this date, dozens of tetrahydrocannabinol derivatives that significantly exceed both D8-THC and D9-THC in terms of biological activity are well-known. These include JWH-051, JWH-057, WH-102, JPG-103, as well as D9-THC-3-dimethylheptyl, cannabinol-3-dimethylheptyl, 1-hydroxy-cannabinol-3-dimethylheptyl, 11-COOH-cannabinol-3-dimethylheptyl. High affinity for CB1 receptors and pronounced biological activity were detected in D8-THC derivatives with various radicals in position 3. All of these agents have the structure of tetrahydrocannabinol. The properties of HU-210 are described in more detail below.

It is known that the excitation process of the cannabinoid receptor involves its interaction with a guanine nucleotide-binding protein (G-protein). Without such interaction, the subsequent modulation of the transductor systems involved in endocannabinoid neurotransmission (adenylate cyclase, mitogen-activated protein kinases, calcium and potassium channels) is impossible.

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The ability of cannabinoid agonists to initiate the interaction of the receptor with the G-protein is usually estimated by the increase in the binding of 35S-guanosine-5'-(- thio) - triphosphate (35S-GTPS). It was found that HU-210 enhanced the binding of 35S-GTPS to human CB1 receptors expressed in various cellular systems, significantly surpassing D9-tetrahydrocannabinol and other CB1 agonists in this indicator. For example, regarding the receptors of the first subtype expressed in HEK-239 cells, the ability of HU-210 to enhance the binding of 35S-GTPS exceeded the indicator for CP-55940 by 11-17 times, and for WIN-55212-2 — by 79 times. Human CB1 receptors were expressed in the same cellular system — in HEK-239 cells. HU-210 effect was 24 times higher than CP-55940 and by 872 times higher than WIN-55212-2. In the preparations of the synaptic membranes of the mouse brain, C57BL/6 HU-210 stimulated the binding of 35S-GTPS more actively in comparison with D9-tetrahydrocannabinol. It surpassed D9-THC by 28 times, CP-55940— by 2 times, WIN-55212-2 —by 59 times, JWH-073—by 12 times. It should be borne in mind that the compounds CP-55940 and WIN-55212-2 are characterized by high biological activity against cannabinoid systems and are widely used in scientific research as effective CB1 receptor agonists.

Cannabinoid inhibition of the adenylate cyclase activity stimulated by forskolin is considered an important neurochemical equivalent of their pharmacological effects. HU-210 was superior in this indicator to the cannabinoids CP-55940, anandamide, WIN-55212-2 and D9-THC, which also indicates a high biological potential of the agent. Thus, the IC50 of D9-tetrahydrocannabinol towards adenylate cyclase (expressed in CHO cells) was 16.51.2 nM, as for HU-210, it was 0.1970.012 nM.

As follows from the above, the classic cannabinoids of list 1 HU-210 have a pronounced affinity for CB1 receptors, surpassing D9-THC in this indicator. This suggests that the psychoactive substance under consideration has a pronounced biological activity and a significant addictive potential, since for cannabinoid agonists, as for agonists of other receptors, a direct correlation between the receptor affinity and the severity of biological effects is observed. In experiments on mice, HU-210 surpassed D9-tetrahydrocannabinol in its ability to inhibit SDA by 2900 times, in its hypothermic action - by 900 times, in its antinociceptive activity - by 240 times.

The high addictive potential of HU-210 was revealed in the first years after its synthesis. In the discrimination test on male Sprague-Dowley rats and pigeons, the addictive activity of HU-210 exceeded the same indicator for D9-THC by 66 and 80 times, respectively. In studies using the method of learning to distinguish (discriminate) substances, the addictive potential of HU-210 was many times higher than that of the high-affinity CB1 agonists CP-55940 and BAY 38-7271, and ten times higher compared to D9-tetrahydrocannabinol.

The effect of non-classical cannabinoids.
There are two stages in the history of studying the properties of CP-47497. Initially, the high biological effectiveness of this drug was determined, including a pronounced addictive potential. It is believed that pharmacological activity of the agent is approximately 10 times higher than that of D9-tetrahydrocannabinol. Later, as new CB1 - and CB2-receptor ligands were introduced, information about the high affinity of the first subtype cannabinoid receptors to CP-47497 and its homologues began to appear. As it is shown, the greatest affinity was detected in CP-47497 and in CP-47497-C8.

Behavioral equivalents at exposures to CP-47497 were first evaluated in the study. The antinociceptive potential of the agent in rodents (methods of squeezing the base of the tail, tail flick test, etc. were used) was comparable to that of morphine and surpassed D9-tetrahydrocannabinol by multiple times. The agent CP-47497appeared to be much more effective when testing inhibition of spontaneous motor activity in rodents, weakening of convulsive activity (electroconvulsive shock), hypothermic action and induction of ataxia in dogs in comparison to D9-THC. Addictive potential (according to results of the discrimination method in rats) was also much higher than the indicator of D9-tetrahydrocannabinol.

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CP-55940, a homologue having n-butanol instead of propanol in position 4 of the cyclohexane ring, shows high biological activity. The affinity of this compound is many times higher than the corresponding indicator for CP-47497 (Ki = 1.12 ± 0.17 nM), and the analgesic activity (evaluated by the writhing test on mice) was more than 4 times higher compared to a similar effect of CP-47497. The antinociceptive effect of another homologue having propyl cyclohexane at position 4 is more than 6 times higher than that of CP-47497, and Ki was 1.30 ± 0.57 nM. When the structure of the CP-55940 molecule was altered with the replacement of cyclohexane ring with cycloheptan, the affinity for CB1 receptors (Ki = 0.17 ± 0.04 nM) and analgesic activity increased (by 16 times).

Aminoalkylindoles, indolylnaphthylmethanes, indenes, pyrroles and other cannabinoids.
The first synthesis of aminoalkylindoles ancestor WIN-55212-2 was carried out in 1991. Then, the high biological activity of WIN-55212-2 was established (in radioligand studies and in experiments on isolated organs), and its addictive potential was also demonstrated (a method of discrimination training). WIN-55212-2 has found wide application as a pharmacological probe of cannabinoid receptors. It is also successfully used as a radio ligand (3H-WIN-55212-2).

The agonistic activity of aminoalkylindoles can be estimated by the increase in the specific binding of 35S-Gtp to the membranes of the rodent brain. It was shown that JWH-073 increased the binding of the GTP analog to the synaptic membranes of the mouse brain by 59% from the basal level, with EC50 = 34 nM. For the D9-THC, corresponding values were 40% and 81 nM, respectively. The agonistic efficacy of other agents was significantly higher: for HU- 210, the maximum gain was 110% at ЕС50= 2.9 nM; the same indicators for CP-55940 - 120% and 6.1 nM; for CP-55244 -120% and 0.12 nM. When using mouse cerebellar membranes as a biological material, JWH-073 binding activity of 35S-GTPgS was lower: the maximum increase reached 53%, ЕС50 = 490 nM. The corresponding values for CP-55940 were 134% and 20 nM; for D9-THC - 54% and 260 nM.

The effects of the "new cannabinoid" groups on the adenylate cyclase activity can be demonstrated by an example of JWH-018. In the study, the cannabinoid effect on the ability to inhibit the adenylate cyclase activity stimulated by forskolin (values in nM; human CB1 receptors and adenylate cyclase are co-expressed in CHO cells) was as follows: CP-55940 = 5,5 ± 2,9; WIN-55212-2 = 38,9 ± 8,2; JWH-018 = 14,7 ± 3,9.

Among the substances of the groups considered, there are agents with a high affinity for cannabinoid receptors. For example, the compound JWH-048 was 4 times higher than D9-ТHK in affinity for CB1-receptors, and in its ability to change vegetative and behavioral indicators (inhibition of SDA, antinociceptive effect, hypothermic effect) was not inferior to the cannabis alkaloid. High affinity for CB1 receptors was also found in JWH-164, JWH-180, JWH-181, JWH-182, JWH-210, JWH-212, JWH-213, JWH-234, JWH-240, JWH-242, JWH-258 and JWH-262. Their constants of inhibition of the specific binding of the CB1 ligand 3H-CP-55940 with the synaptic membranes of the rodent brain were 6.6 ± 0.7 nM; 26 ± 2 nM; 1.3±0.1 nM; 0.65 ± 0.03 nM; 0.46 ± 0.03 nM; 33.0 ± 0.9 nM; 1.5 ± 0.2 nM; 8.4 ± 1.8 nM; 14 ± 1 nM; 42 ± 9 nM; 4.6 ± 0.6 nM and 28 ± 3 nM, respectively.

A similar indicator for D9-tetrahydrocannabinol was 41 ± 2 nM. Aminoalkylindole JWH-398 (1-pentyl-3-(4-chloro-1-naphthol)indole was isolated from smoking mixtures. The affinity for CB1 receptors of this agent is high (Ki = 2.3 nM).

1-pentyl-3-phenylacetylindoles (do not contain naphthalene radical) were superior in affinity for CB1 receptors than D9-tetrahydrocannabinol: JWH-203-5.1 times; JWH — 204-3.2 times; JWH — 249-4.9 times; JWH — 250-3.7 times; JWH — 251-1.4 times; JWH — 252-1.8 times; JWH — 302-2.4 times; JWH — 305-2.7 times; JWH — 306-1.6 times; JWH — 311-1.8 times.

BAY 38-7271, a compound synthesized in the laboratory of the German company Bayer AG, has a high affinity for the receptors of the first subtype. The values of 3H-BAY 38-7271 dissociation constant in radioligand experiments with synaptic membranes of rat and human brains, as well as with cloned human CB1 receptors, ranged from 1.84-2.91 nM. In a parallel series of experiments, similar values were obtained for a generally recognized ligand 3H-CP-55940. BAY 38-7271 in terms of agonistic efficacy (assessed by the degree of increased 35S-Gtp binding to the synaptic membranes of the human cerebral cortex and the whole rat brain), it was many times superior than D9-tetrahydrocannabinol. The biological activity of BAY 38-7271 (the ability to cause hypothermia in rats after intraperitoneal or intravenous injection) is defined as lower in comparison with the same indicator for HU-210, but it was comparable to that of CP-55940 and WIN-55212-2. Under similar experimental conditions, it was significantly inferior comparing to BAY 38-7271 in terms of hypothermic activity. Addictive potential of BAY 38-7271 was evaluated on rats using the distinction (discrimination) method of substances, it was lower in comparison with similar indicators for HU-210 and CP-55940, but it was ten times higher than the corresponding parameter for D9–tetrahydrocannabinol. All the listed behavioral equivalents of cannabinoids were prevented by CB1-receptor antagonists rimonabant (SR-141716A). This indicates that the addictive effects are realized through the receptors of the first subtype.

Clinical aspects of the effect on the body.
CB1 receptors belong to the family of G-protein-bound receptors and are widely distributed in areas of the brain which functions are associated with the control of motor activity, cognitive functions, emotional reactions, motivated behavior and homeostasis. Regarding the psychoactive effect, the ligands of the cannabinoid receptors of the first subtype are the most important ones. Their activation is represented by euphoria, sedation, decrease in spontaneous motor activity(SDA), antinociceptive effects, hypothermia, catalepsy. The combination of these behavioral and physiological equivalents forms the basis of the addictive potential of cannabinoids. If we are talking about the impact on the mental state of a person, we can also add a hallucinogenic effect to this list.

CB2 receptors are located mainly in immune cells, both inside and outside the central nervous system. The functioning of these receptors involves the modulation of cytokine emission and migration of immune cells. In the brain, CB2 receptors are present in microglia, blood vessels, and some neurons.

Psychoactive substances, which are a part of the "spice" composition, have a strong effect on most body systems. Brain damage is the most pronounced. Smoking the composition leads to an acute spasm of the cerebral vessels — this happens reflexively in order to reduce the passage of toxic substances into the brain tissue. Vasoconstriction leads to hypoxia, reduced viability of brain cells and their death.

Also, smoking mixtures has a great influence on the central nervous system. The effect of smoke ingredients on the central nervous system causes addiction to smoking "spice". A result, various reactions can manifest: a state of euphoria, unprovoked hysteria or bursts of laughter, coordination and orientation disorders, visual and auditory hallucinations, an absolute loss of the ability to control one's behavior. All these reactions of central nervous system already threaten human life when manifested. There are a huge number of cases when people, being under the influence of drugs consisting of these mixtures, jumped from the last floor of a high-rise building or swam in icy water.

With regular smoking of "spice", irreversible disorders of the central nervous system occur. There may be persistent attention disorders, weakened memory and a decrease in intelligence, a tendency to depression and suicide. Among other things, smokers of "spice" have a very high risk of becoming disabled due to severe lesions of the central nervous system.

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If toxic substances are present in smoke, toxic reactions may occur — nausea and vomiting, rapid heartbeat and high blood pressure, spasms and convulsions, fainting and coma. The difficulty in eliminating the consequences of smoking spice mixtures is that in many cases, narcotic compounds are not detected in the blood of patients during the tests, which significantly complicates the diagnosis and appropriate treatment. The systematic use of such smoking mixtures provokes physical and mental adaptation. As a result, withdrawal syndrome causes such symptoms as body aches, nausea, fever. Smoking a mixture also leads to a mental disorder. Memory, mental activity, and attention are threatened. According to other clinical observations, long-term use of "spice" has a negative impact on the liver, sexual and cardiovascular systems. Smoking "spice" also affects the erection, slows down the motility of spermatozoa and disrupts the menstrual cycle in women. Long-term use of synthetic cannabinoids as part of smoking mixtures can provoke the development of cancer and mental disorders.

The liver also suffers greatly. Its cells are exposed to the damaging effects of the toxic components of spice, especially dangerous in case of an overdose, which is not a rare occurrence. Some of the harmful substances are neutralized by the liver cells, and a large number of the cells die in the process; and the rest of the substances are carried in the blood through the body. The effect on the excretory system is reflected to a great extent in the kidney damage. When the remnants of toxic substances are excreted in the urine, the kidney parenchyma is damaged, and sclerosis is formed (replacement by connective tissue). The active substances of smoking mixtures enter the body through the lungs together with the smoke when it is inhaled. Most of the substances is passed through the walls of the pulmonary capillaries, enters the bloodstream almost freely and spreads throughout the body.

Thus, while monitoring the smoking mixtures composition, it was noticed that all types of synthetic cannabiтoids have different effects on the body's receptors, so it is impossible to say when an overdose occurs. Psychoactive substances, that are part of the" spice ", affect the cannabinoid receptors — CB1 and CB2, belonging to the endocannabinoid signaling system. Moreover, depending on the composition of the mixture, the effect is different. For example, the compound O2-propan-9β-oxy-11-norhexahydrocannabinol, which has a high affinity for the cannabinoid receptors of the first subtype and has agonistic activity in vitro experiments, was minimally active in experiments on mice (evaluation of sedative, antinociceptive, cataleptogenic and hypothermic effects). Cannabinoid 3-(1', 1' - dimethylethyl)-D8-THC belongs to the high affinity ligands of CB1-receptors (it exceeds D9-THC by 3 times in affinity), but does not have biological activity. With regular use of "spice", the whole body suffers. The liver functions are disrupted, the functions of the central nervous system are depressed, the organs of the excretory and respiratory systems suffer as well.

 
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