Pharmacokinetics, systemic toxicity, thermoregulation and acute behavioural effects of 25CN-NBOMe.

N-(2-methoxybenzyl)phenethylamines (NBOMes) are a family of potent 5-HT2A agonists containing substances emerging on the illicit drug market as a replacement for N,N-diethyllysergamide (LSD). Despite the increasing use of NBOMes for diagnostic, research and recreational purposes, only a limited number of studies have focussed on their in vivo effect. Here, we investigated pharmacokinetics, systemic toxicity, thermoregulation in individually and group-housed animals, and acute behavioural effects after subcutaneous administration of 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe; 0.2, 1, and 5 mg/kg) in Wistar rats. Drug concentration peaked 1 h after the administration of 5 mg/kg in both blood serum and brain tissue with a half-life of 1.88 and 2.28 h, respectively. According to Organisation for Economic Co-operation and Development 423 toxicity assay, the drug is classified into category 3 with a lethal dose of 300 mg/kg and an estimated LD50 value of 200 mg/kg. Histological examination of organs collected from rats injected with the lethal dose revealed subtle pathological changes, highly suggestive of acute cardiovascular arrest due to malignant arrhythmia. Altered thermoregulation after 5 mg/kg was demonstrated by reduced body temperature in individually housed rats (p < 0.01). Behavioural effects assessed by the Open Field test and Prepulse Inhibition of Startle Response revealed that the two lower doses (0.2 and 1 mg/kg) caused a reduction in locomotor activity (p < 0.01), increased anxiety (p < 0.05) and 5 mg/kg additionally impaired sensorimotor gating (p < 0.001). In summary, 25CN-NBOMe readily passes the blood-brain barrier and exhibits a moderate level of toxicity and behavioural effect comparable with other NBOMes.

Novel D2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment.

Schizophrenia is a serious mental disorder without a fully understood pathomechanism, but which involves dysregulation of neurotransmitters and their receptors. The best option for the management of schizophrenia comprises so-called multi-target ligands, similar to the third generation of neuroleptics. Dopamine type 2 receptors (D2Rs) are the main target in the treatment of schizophrenia, in particular for mitigation of the positive symptoms. Due to the high expression of 5-hydroxytryptamine type 3 receptors (5-HT3Rs) in human brain areas responsible for emotional behavior, motivation, and cognitive function, 5-HT3Rs represent a potential target for modulating the cognitive and negative symptoms of schizophrenia. Here we present the design, synthesis, and both in vitro and in vivo biological evaluation of 1,4-disubstituted aromatic piperazines. Screening of in vitro properties revealed the two most promising drug candidates (21 and 24) which were found to be potent D2Rs and moderate 5-HT3R antagonists, and which were forwarded to in vivo studies in Wistar rats. Considering toxicity, administration of the maximal feasible dose of 21 (2 mg/kg) did not produce any side effects. By contrast, the higher solubility of 24 led to revelation of mild and temporary side effects at the dose of 20 mg/kg. Importantly, both 21 and 24 showed facile crossing of the blood-brain barrier, even exerting higher levels in the brain in comparison to plasma. In a behavioral study using the acute amphetamine model of psychosis, we showed that compound 24 ameliorated both positive and negative effects of amphetamine including hyperlocomotion, social impairments, and disruption of prepulse inhibition. The effect of the highest dose (10 mg/kg) was comparable to the effect of the reference dose of aripiprazole (1 mg/kg).

Pharmacokinetic, pharmacodynamic, and behavioural studies of deschloroketamine in Wistar rats.

BACKGROUND AND PURPOSE: Deschloroketamine (DCK), a structural analogue of ketamine, has recently emerged on the illicit drug market as a recreational drug with a modestly long duration of action. Despite it being widely used by recreational users, no systematic research on its effects has been performed to date. EXPERIMENTAL APPROACH: Pharmacokinetics, acute effects, and addictive potential in a series of behavioural tests in Wistar rats were performed following subcutaneous (s.c.) administration of DCK (5, 10, and 30 mg·kg-1 ) and its enantiomers S-DCK (10 mg·kg-1 ) and R-DCK (10 mg·kg-1 ). Additionally, activity at human N-methyl-d-aspartate (NMDA) receptors was also evaluated. KEY RESULTS: DCK rapidly crossed the blood brain barrier, with maximum brain levels achieved at 30 min and remaining high at 2 h after administration. Its antagonist activity at NMDA receptors is comparable to that of ketamine with S-DCK being more potent. DCK had stimulatory effects on locomotion, induced place preference, and robustly disrupted PPI. Locomotor stimulant effects tended to disappear more quickly than disruptive effects on PPI. S-DCK had more pronounced stimulatory properties than its R-enantiomer. However, the potency in disrupting PPI was comparable in both enantiomers. CONCLUSION AND IMPLICATIONS: DCK showed similar behavioural and addictive profiles and pharmacodynamics to ketamine, with S-DCK being in general more active. It has a slightly slower pharmacokinetic profile than ketamine, which is consistent with its reported longer duration of action. These findings have implications and significance for understanding the risks associated with illicit use of DCK.

Effects of synthetic cathinone naphyrone in the conditioned place preference test - Evidence of its addictive potential.

Naphyrone, also known as NRG-1, is a novel psychoactive substance (NPS), a cathinone with stimulatory properties available on the grey/illicit drug market for almost a decade. It is structurally related to infamously known powerful stimulants with the pyrovalerone structure, such as alpha-pyrrolidinovalerophenone (α-PVP) or methylenedioxypyrovalerone (MDPV) that are labeled as a cheap replacement for cocaine and other stimulants. Despite the known addictive potential of α-PVP and MDPV, there are no studies directly evaluating naphyrone's addictive potential e.g., in conditioned place preference (CPP) test or using self-administration. Therefore, our study was designed to evaluate the addictive potential in a CPP test in male Wistar rats and compare its effect to another powerful stimulant with a high addictive potential - methamphetamine. Naphyrone increased time spent in the drug-paired compartment with 5 and 20 mg/kg s.c. being significant and 10 mg/kg s.c. reaching the threshold (p = 0.07); the effect was comparable to that of methamphetamine 1.5 mg/kg s.c. The lowest dose, naphyrone 1 mg/kg s.c., had no effect on CPP. Interestingly, no dose response effect was detected. Based on these data, we are able to conclude that naphyrone has an addictive potential and may possess a significant risk to users.