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AB-CHMINACA

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AB-CHMINACA - is a synthetic cannabinoid receptor agonist (SCRA), which has the structure of aminoalkylindazol. It is used as an active ingredient in products sold as cannabis alternatives because its subjective effects are similar to that of cannabis. It was synthesized by a company Pfizer and patented in 2009 as a potential anaesthetic agent; however, there is no data on its clinical application. To this date, AB-CHMINACA doesn't have any known therapeutic or medical application. It is used recreationally in different regions. Moreover, some countries put the substance under national control. According to EMCDDA there are a lot of cases of deaths, which were found to have lethal concentrations in postmortem biological samples with an index from 0.32 to 12 ng/ml with a median of 3.6 ng/ml. Eighteen countries report this substance to be under control, according to the law, they are: Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, France, Germany, Hungary, Italy, Latvia, Lithuania, Luxembourg, Finland, Slovenia, Slovakia, Sweden, Turkey and the United Kingdom. In the USA, the substance is listed as Schedule l by DEA. The biggest seizure of AB-CHMINACA in plant materials was carried out by law enforcement agencies in Spain. This large-scale operation was carried out in Alicante in March 2016, a total of 145,157 packages were seized, each of them contained from 1 to 3 grams of plant material (which, in turn, contained synthetic cannabinoids AMB-FUB and AB-FUBINACA) and 2 bags (2 kg each, containing AMB-FUB as well). Information, passed to EMCDDA and Europol, indicates that the substance was usually seized in the form of plant material and, to a lesser extent, in form of powder. Also, it was reported about a number of major seizures of powder in Luxembourg (4.8 kg), France(3.5 kg) and Spain (about 2 kg).

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Potential precursors of the substance are 1H-indole-2,3-dione, 1H-indazole-3-carboxylic acid, methyl or other alkyl ester, 1H-indazole-3-carboxylic acid esters, L-valinamide and (bromomethyl)cyclohexane. Some of them are commercially available. It is important to note, that L-valinamide is produced from inexpensive natural sources or produced by industrial fermentation. Since this reagent is used for the synthesis of S-enantiomer, it can be assumed that this very form of AB-CHMINACA is likely to be common on European market in the future. Commercially available household or industrial products, which can be used for synthesis, can also contain potentially toxic substances, including heavy metals and organic solvents, which can lead to serious toxicity when using the resulting impure product.

The name of N-(1-Amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide comes from its structural features: a methyl-aminobutanone-bound group, a cyclohexyl methyl tail, an indazole core and a carboxamide linker. AB-CHMINACA has a stereogenic centre, that is why there are 2 possible enantiomers: (R)- and (S)-AB-CHMINACA. S-form was initially described in patent application of Pfizer inc. and published in 2009. It is important to note that compounds described in a patent documentation, involve only S-configuration of the substance. Other street names, which are reported by EMCDDA, include the following: Aromatic Pot Pourri, Jamaican Gold Supreme, Jamaican Gold Extreme, Yama, Bonzai Summer Boost, Bonzai Winter Boost, Bonzai Citrus, Blaze, Bubblegum, Manga Xtreme, Manga XXL, V.I.P., Love, R&B, King Size Slim Rolling Papers, Vertex Ultra-Extreme Incense Pirate Edition, Mary Jean, Waldemar Uszkiewicz Taak, Vertex Pirate Edition Ultra-Extreme Incense, Galaxy Herbal Incense: Althea officinalis, Matt Hardener, Aura mystic Bulc.

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In its pure form, AB-CHMINACA has the appearance of white or yellowish-white crystal powder. It is well-soluble in ethanol, DMSO and DMF are approximately 3, 10 and 5 mg/ml, respectively. Substance is poorly soluble in water buffers. The melting point is about 85 °C, there is no data on the boiling point, but it can be assumed that it is at least 350 °C. Data from samples obtained as a result of seizures shows that AB-CHMINACA is usually found in herbal/plant materials. There were also other forms, including powders. Patent of Pfizer inc. involved synthetic cannabinoid application as a part of various pharmaceutical compositions, depending on the methods of administration. To make a smoking mixture, the substance is dissolved in an organic solvent (e.g. acetone) and is applied on plant material (e.g. Turnera diffusa or Althaea officinalis) – either by spraying or soaking followed by evaporation of the solvent.

Pharmacokinetics and pharmacodynamics.
In studies on human liver microsomes (HLMs) 26 metabolites of AB-CHMINACA were identified by LC-TOF-MS. The main metabolites were formed by mono-hydroxylation of the cyclohexyl ring and hydrolysis of the outer amide group to form a carboxylated metabolite. In addition, six dihydroxylated metabolites, five monohydroxylated metabolites and five glucoronated metabolites were formed. An interesting result is that glucoronidation occurs at the carboxyl group, and not at one of the hydroxyl groups formed during the first phase of metabolism. rCYP3A4 was the main cytochrome enzyme involved in the metabolism of this substance. A key role of CYP3A4 in AB-CHMINACA metabolism in vitro suggests that subchronic use of the substance can have numerous toxic consequences on the body. In comparative studies on metabolism of compounds related to this substance (AB-PINACA, AB-FUBINACA, ADB-FUBINACA and AKB-48) significant coincidences and minor differences in the mechanisms of metabolism were revealed. Firstly, hydrolysis of the terminal amide group by amidase is the main pathway of their metabolism (except for AKB-48); secondly, the formation of several mono or dihydroxylated metabolites of the nonaromatic terminal ring or terminal pentyl chain is also their main mechanism, except for AB-FUBINACA, its indazole ring is not a part of the mainly metabolized substrate.

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The unchanged substance can be found in many parenchymal human organs, as well as in subcutaneous fat, but not in plasma or urine, where, in fact, it is possible to identify such metabolites as 4-hydroxycyclohexylmethyl and N-[[1-(cyclohexylmethyl)-1H-indazol-3-yl]-carbonyl]-l-valine at a concentration of 52.8 and 41.3 ng/ml, respectively. It was found that more than one glucoronated metabolite can be formed from a substrate having only one site of the supposed glucoronation (e.g. М25 and М26 from М21). This fact can be explained by intramolecular rearrangement of 1-β-O-acyl glucuronide as a result of migration of acyl group at the position of C2, C3 or C4 compounds. The isomerization rate is affected by a number of parameters, including the structure of the aglycone, which may also explain why in studies there is only one glucoronidated metabolite formed from M20. In studies of Wiley on biochemical effects of this substance in vitro and on pharmacological effects in vivo it was revealed that AB-CHMINACA replaces [3H]CP55,940 at the binding site of the CB1 receptor with the inhibition constant (ki)0.78 nM for AB-CHMINACA and 0.59 nM for СР55,940. During the analysis of stimulated [35S]GTPg higher effectiveness was demonstrated compared to that of СР55. It was approximately 3 times more, and the affinity to CB1 receptor for AB-CHMINACA was 0.45 nM. This substance causes 40 times stronger dose-dependent suppression of spontaneous activity, antinociception, hypothermia and immobility, than 9-THC does (according to the research in the tetrad tests for the study of the cannabinoid effects profile). Cannaert in study on hCB1 and hCB2 activation, including recruitment of β-arrestin, determined a higher potency of the substance than that of other similar synthetic cannabinoids with an indicator hCB1 EC50 = 6.1 nM; hCB2 EC50 = 3.7nM. It is known that on black market synthetic cannabinoids can be contaminated by N2-cyclohexylmethyl regioisomer, so, according to a recent comparative functional study on a cloned human CB1 receptor material, AB-CHMINACA is a full agonist and is approximately 500 times more active than partial agonist N1-alkylated isomer: respective indicators of EC50 are 7.8 and 4080 nM. As it is known for synthetic cannabinoids of ” new generation” (for example, JWH-018, JWH-073) and 11-hydroxy-THC it is quite likely that some of monohydroxylated metabolites of AB-CHMINACA remain active in regard to CB1 receptor, which suggests their contribution to the pharmacological profile of this compound. During in vitro receptor activity screening using authentic human urine samples confirmed the presence of metabolites of this substance, it was revealed that several metabolites retain the ability to activate cannabinoid receptors, although at a lesser extent. However, in case of CB1 activity it is unclear, whether the metabolites can pass through the blood-brain barrier and reach effective concentrations in the brain tissue. For instance, the amide cleavage product shows low affinity for the CB1 receptor, and, unlike this type of receptors, CB2 receptors are mainly expressed on the cells of the immune system and do not seem to contribute to psychoactive properties. At the moment, there is no data on AB-CHMINACA influence on other pharmacological (receptor or enzyme) targets. Biological properties of the metabolites are also unknown.

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Clinical effects, methods of use and doses.
Whole body, mild indistinct skin tingling, a decrease in surface tactile sensitivity, and given that this effect is dose-dependent, with an increase in the dose, uncontrolled defocusing of attention and this sensation may occur with a complete loss of motor control; pronounced sedative effect; emotional changes with anxiety reduction and the appearance of very weak euphoria or pronounced empathy, that is a stabilization of a separate existing emotion and enhancing it the nominal one that a person is experiencing at the moment of use; "immersion enhancement" effect is described as a tendency of a person to fully delve into the current type of activity that he is engaged in; "changes in felt gravity" is characterized by slow and smooth sensations of flight or wave-like illusions of body swaying, a change in position and a slight loss of proprioception orientation; the appearance of visual effects with elements of distortion of static objects, turning them into dynamic objects changing in projection, the appearance of "ripples" or "clouds / fog" in the surrounding world at the time of use; enhanced sound perception, attraction to favorite music; an increase in visual acuity and brightness; conceptual thinking.

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Undesirable negative effects include: impaired motor activity, tachycardia, dry mouth, conjunctival injection or "red eyes", nausea, vomiting, confusion, hallucinations, paranoia, fear, anxiety, distorted perception of time, lethargy, depersonalization / derealization. At high doses there is a high risk of developing paradoxical bradycardia, chest pain, myocardial infarction, convulsions, hypertension, vomiting, convulsions, hyperthermia, psychosis, aggressive behavior, violent behavior, suffocation/aspiration of vomit, uncontrolled agitation. There is data on delayed effects of acute toxicity due to AB-CHMINACA, for example, the most frequent symptoms of systemic post-effects included: acute psychosis, which resulted in self-harm (mutilation of one's own body), acute renal failure, prolonged depersonalization /derealization (for one year) with episodes of panic attack. Unfortunately, there are no studies on addiction and long-term abuse of this substance in humans. However, it is assumed that AB-CHMINACA induces tolerance to the substance and symptoms, similar to a withdrawal on discontinuation of regular use in small doses. Recently, in Poisons Information Centre Freiburg 2 cases of withdrawal syndrome after use of this substance were reported, which were characterized by anxiety, unstable mood, sudden uncontrollable crying, a feeling of inner emptiness, mild spatial disorientation, hyperacusis, somatic pain, shortness of breath, hyperventilation, intense sweating and a feeling of motor and internal anxiety.

Use of the substance by people with mental illness is strongly prohibited. As for potential addiction, mental dependence on the substance occurs exclusively with long-term repeated use. There is data on possibility of withdrawal syndrome occurrence, which is characterized by distorted mood, tremor in the extremities, increased anxiety, subdepressive state, spontaneous increase in heart rate and panic attacks, and the above symptoms are leveled within 2-3 months of abstinence without the pharmacological therapy.

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As a rule, this substance is administered by smoking mixtures. Considering the fact that it is impossible to differentiate doses of the substance from a number of plant materials, it is recommended to start with minimum doses. The starting dose, which is associated with effects of intoxication, is 1.3-2 μg/kg, medium doses range from 2 to 4.5 μg/kg, high and extremely high doses are in range from 5 to 10 μg/kg. Taking into consideration high risk of side effects (including lethal outcome), loss of control over the physical and mental state of the body, it is categorically not recommended to use high doses. When administered by inhalation, manifestation of effects occurs after 5-10 minutes and their duration is 1-3 hours. Depending on the dose, post-effects can remain up to 10 hours. When administered orally (e.g. by means of gelatin capsules), the time of onset of effects varies from 10 to 30 minutes, they can last for a long time (about 5 hours), depending on many factors and metabolism. The most dangerous combinations of drugs, which can cause severe side effects or irreversible physical/mental damage: 2C-Tx, 2C-x, 5-MeO-xxT, amphetamines, cocaine, aMT, DMT, DOx, LSD, mescaline, mushrooms, 25-x-NBOMe.​

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