Severe Toxicity to the New Psychoactive Substances 3-Hydroxyphencyclidine and N-Ethylhexedrone: an Analytically Confirmed Case Report.

INTRODUCTION: 3-Hydroxyphencyclidine (3-HO-PCP) is a new psychoactive substance (NPS) and a hydroxy derivative of phencyclidine (PCP), and N-ethylhexedrone (Hexen) is a synthetic cathinone. We describe an analytically confirmed case of acute toxicity related to the use of both 3-hydroxyphencyclidine and N-ethylhexedrone. CASE REPORT: A 56-year-old male was brought to the Emergency Department by ambulance with hyperthermia (39.9 °C), sinus tachycardia (150 beats per minute), reduced consciousness, ocular clonus, and vertical nystagmus. He was treated with cooled intravenous (IV) fluids and IV benzodiazepines. Following 1 hour of treatment, his temperature fell to 37.7 °C, he developed rhabdomyolysis (creatine kinase peaked at 5999 IU (normal range < 229 IU)): he was managed with supportive measures and was discharged after 25 hours. The patient admitted regular use of Hexen and recent use of 3-HO-PCP. Analysis of urine and serum identified 3-hydroxyphencyclidine and metabolites, N-ethylhexedrone and metabolites, and clephedrone and metabolites. DISCUSSION: This is a case of analytically confirmed toxicity to 3-HO-PCP and N-ethylhexedrone. The acute toxicity reported in this patient is consistent with the use of 3-HO-PCP, but there were sympathomimetic and serotonergic features potentially consistent with the cathinone N-ethylhexedrone. The description of the acute toxicity of NPS, such as these, is vital to aid medical toxicologists and emergency medicine physicians treating patients who use them.

New Amine and Aromatic Substituted Analogues of Phencyclidine: Synthesis and Determination of Acute and Chronic Pain Activities.

BACKGROUND: Phencyclidine (PCP, I) is a synthetic drug with remarkable physiological properties. PCP and its analogues exert many pharmacological activities and interact with some neurotransmitter systems in the central nervous system like particular affinity for PCP sites in NMDA receptors or dopamine uptake blocking or even both. AIM AND OBJECTIVE: The following research, methyl group with electron-donating and dipole moment characters was added in different positions of phenyl ring along with the substitution of benzylamine (with many pharmacological effects) instead of piperidine ring of I to produce new compounds (II-V) of this family with more analgesic activities. MATERIALS AND METHODS: Analgesic activities of these new compounds were measured by tail immersion and formalin tests for acute and chronic pains, respectively. Also, the outcomes were compared with control and PCP (10 mg/kg) groups. RESULTS: The results indicate that compounds III, IV, and V have more acute and chronic antinociceptive effects than PCP and compound II which may be concerned with more antagonizing activities of these new painkillers for the blockage of dopamine reuptake as well as high affinity for NMDA receptors PCP binding site. CONCLUSION: It can be concluded that the benzylamine derivative of phencyclidine with a methyl group on the benzyl position on phenyl ring (V) is a more appropriate candidate to reduce acute and chronic (thermal and chemical) pains compared to other substituted phenyl analogs (II-IV) and PCP.

Syntheses, analytical and pharmacological characterizations of the 'legal high' 4-[1-(3-methoxyphenyl)cyclohexyl]morpholine (3-MeO-PCMo) and analogues.

New psychoactive substances (NPS) are commonly referred to as 'research chemicals', 'designer drugs' or 'legal highs'. One NPS class is represented by dissociative anesthetics, which include analogues of the arylcyclohexylamine phencyclidine (PCP), ketamine and diphenidine. A recent addition to the NPS market was 4-[1-(3-methoxyphenyl)cyclohexyl]morpholine (3-MeO-PCMo), a morpholine analogue of 3-MeO-PCP. Although suspected to have dissociative effects in users, information about its pharmacological profile is not available. From clinical and forensic perspectives, detailed analytical data are needed for identification, especially when facing the presence of positional isomers, as these are frequently unavailable commercially. This study presents the analytical and pharmacological characterization of 3-MeO-PCMo along with five additional analogues, namely the 2- and 4-MeO-PCMo isomers, 3,4-methylenedioxy-PCMo (3,4-MD-PCMo), 3-Me-PCMo and PCMo. All six arylcyclohexylmorpholines were synthesized and characterized using chromatographic, mass spectrometric and spectroscopic techniques. The three positional isomers could be differentiated and the identity of 3-MeO-PCMo obtained from an internet vendor was verified. All six compounds were also evaluated for affinity at 46 central nervous system receptors including the N-methyl-d-aspartate receptor (NMDAR), an important target for dissociative anesthetics such as PCP and ketamine. In vitro binding studies using (+)-[3-3 H]-MK-801 in rat forebrain preparations revealed moderate affinity for NMDAR in the rank order of 3-Me >3-MeO > PCMo >3,4-MD > 2-MeO > 4-MeO-PCMo. 3-MeO-PCMo was found to have moderate affinity for NMDAR comparable to that of ketamine, and had an approximate 12-fold lower affinity than PCP. These results support the anecdotal reports of dissociative effects from 3-MeO-PCMo in humans.

Synthesis and Antinociception Activities of Some Novel Derivatives of Phencyclidine with Substituted Aminobenzothiazoles.

BACKGROUND: Phencyclidine (PCP) as well as the analogues has indicated several pharmacological behaviors like analgesic, anticonvulsant, antianxiety, antidepressant depending on the dose and species examined. They interact with some neurotransmitter systems in the central nervous system like particular affinity for PCP sites in NMDA receptors or dopamine uptake blocking or both. OBJECTIVE: Due to analgesic properties of aminobenzothiazoles family, piperidine ring of PCP was replaced with electron-donating and electron-withdrawing substituted aminobenzothiazoles (1-4) for obtaining new analogues (II-V) with more analgesic activities. METHODS: Synthesis of new compounds (II-V) and measuring the acute and chronic pain properties of them were carried out through applying tail immersion &formalin tests on mice and the outcomes compared with control & PCP groups at dosage of 10 mg/kg. RESULTS: III & V with substituted methoxy and methyl-aminobenzothiazoles indicated better activity to lessen acute and chronic (thermal and chemical) pains compared with unsubstituted & phencyclidine animal groups. CONCLUSION: Methoxy and methyl-aminobenzothiazole derivatives" of phencyclidine revealed more analgesic activities compared with other groups which may concern to close affinity for DA uptake blocking as well as NMDA receptors in this family.

The evolving high: new designer drugs of abuse.

Over the past decade, emerging drugs of abuse and synthetic derivatives of more traditional agents have flooded the market. While Europe was the first to experience a surge in the use of drugs such as synthetic cathinones and cannabinoids, poison centers throughout the United States have seen a dramatic rise in calls related to these new designer drugs of abuse. In the majority of cases, care is largely supportive but significant medical and traumatic complications may occur. Providers must be aware of the ever-changing trends in abuse, so that they may optimally care for poisoned patients.

Synthesis and pain perception of new analogues of phencyclidine in NMRI male mice.

Phencyclidine (PCP, I) and many of its derivatives have demonstrated many pharmacological effects. They interact with a number of neurotransmitter systems within the central nervous system. For example, Phencyclidine is a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) subtype of the glutamate receptor, and it causes the release and inhibits the reuptake of monoaminergic neurotransmitters, including dopamine, serotonin and norepinephrine. In this study, new thienyl (TCP, II), as well as benzothiophen (BTCP, III) derivatives (IV-VII) were synthesized. The acute and chronic pain activities of these drugs were studied using the tail immersion and formalin tests on mice and the results were compared with PCP, TCP and control groups at dosage of 10 mg/kg. The results indicated that the drug VII produced more analgesic effects on acute chemical pain in formalin test compared with other drugs. In addition, this analgesic effect was remarkably seen for drugs II, VI and VII in chronic pain in the mentioned test in comparison with other drugs. Also, the results showed that acute thermal pain could be diminished by drugs VI, II and I compared with other drugs in tail immersion test. It can be concluded that more analgesic effects of new BTCP analogues (VI and VII) may be concerned with antinociception activities of benzothiophene group and also with binding to cocaine site on the dopamine transporter receptor which seems to be more potent than PCP receptor in decreasing pain.

Preparation and analytical characterization of 1-(1-phenylcyclohexyl)piperidine (PCP) and 1-(1-phenylcyclohexyl)pyrrolidine (PCPy) analogues.

Classic examples of psychoactive arylcycloalkylamines include ketamine and 1-(1-phenylcyclohexyl)piperidine (PCP) and many others serve as important structural templates for neuropharmacological research. The recent emergence of PCP analogues that can be obtained from internet retailers requires the implementation of appropriate monitoring strategies for harm reduction purposes. Access to analytical data plays a key part when encountering these substances, especially if reference material is not available. The present study describes the synthesis of three substituted 1-(1-phenylcyclohexyl)piperidines, (3-MeO-, 4-MeO- and 3-Me-PCP) and three substituted 1-(1-phenylcyclohexyl)pyrrolidine analogues (3-MeO-, 4-MeO- and 3-Me-PCPy). Analytical characterizations of all six arylcyclohexylamines and their primary 1-phenylcyclohexanamine intermediates included gas chromatography ion trap electron- and chemical ionization and high resolution mass spectrometry, liquid chromatography electrospray hybrid triple-quadrupole linear ion trap tandem mass spectrometry, infrared, diode array detection and (1) H and (13) C nuclear magnetic resonance (NMR) spectroscopy. Solvent (CDCl3 vs. d6 -DMSO) and protonation effects (free bases vs hydrochloride salts) were studied in order to investigate the impact on shifts and splitting patterns, for example, when attempting to assign separate axial and equatorial proton chemical shifts of NMR spectra. Differentiation between the isomeric 3-MeO-/4-MeO-PCP and PCPy analogues was feasible under mass spectral conditions. Gas chromatography analysis appeared to induce notable degradation of the 4-MeO-substituted analytes, especially when dealing with the HCl salts which led to the detection of the substituted 1-phenylcyclohex-1-ene nucleus. This phenomenon was observed to be less pronounced with the 3-MeO isomers, possibly due to the resonance properties of the para-methoxy group followed by more facile elimination of the amine.

Synthesis and antinociceptive behaviors of new methyl and hydroxyl derivatives of phencyclidine.

Phencyclidine (I) and its derivatives show such pharmacological behaviors as analgesic, anticonsulvant, anti-anxiety and antidepressant, while interacting with central nervous system. In this study, new methyl and hydroxyl derivatives of PCP were synthesized and their antinociceptive behaviors in animals were examined by measuring the number of writhing in a writhing test of visceral pain and the pain scores in Formalin test. Compared to control and PCP groups, findings in experimental groups indicated the new synthesized analogues (compounds II, III and V, 10 mg/kg) of PCP were able to produce more analgesic effects in formalin and writhing tests, especially for compound V. It was concluded that the new synthesized derivatives of PCP could substantially and respectively diminish acute and chronic pains.

Synthesis and analgesic effects of new pyrrole derivatives of phencyclidine in mice.

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, CAS 956-90-1, PCP, I) and many of its analogues have shown some pharmacological effects. In this study, new pyrrole derivatives of I (1-(1-phenylcyclohexyl)pyrrole, II and 1-[1-(4-methylphenyl)(cyclohexyl)]pyrrole, III) and their intermediates were synthesized and the acute and chronic pains were examined on mice using tail immersion (as a model of acute thermal pain) and formalin (as a model of acute and chronic chemical pain) tests and the results were compared with the PCP and control groups. The results indicated that III generated higher analgesic effects in the tail immersion test compared to the PCP and control (dimethyl sulfoxide, DMSO) groups, demonstrating a marked and significant increase in tail immersion latency, but this effect was not observed for II in the dose of 1 mg/kg. The formalin test showed that III was effective in acute chemical pain (phase I, 0-5 min after injection), but was not effective for II at the same dosage compared to the PCP and control groups. Also chronic pain will be significantly attenuated by III but II was not effective as compared to the other groups. It is concluded that substitution of the aromatic pyrrole ring instead of piperidine in the PCP molecule will not be effective alone in tail immersion and formalin tests but the addition of a methyl group (with high electron donating and dipole moments) on the phenyl group plus substitution of the aromatic pyrrole ring can be effective in acute and chronic pain compared to the PCP and control groups.

Synthesis and determination of acute and chronic pain activities of 1-[1-(4-methylphenyl) (cyclohexyl)] morpholine as a new phencyclidine derivative in rats.

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, CAS 77-10-1, PCP, I) and many of its analogues have been synthesized and their pharmacological properties studied. In this research, new methyl morpholine derivative of phencyclidine (1-[1-(4-methylphenyl) (cyclohexyl)]morpholine, Methyl-PCM, III) was synthesized and the acute and chronic pain activities were studied using tail immersion and formalin tests on rats and compared to PCP and PCM (1-(1-phenylcyclohexyl)morpholine, CAS 2201-40-3, PCP-morpholine, II). The results Indicated that Methyl-PCM (III, 6 mg/kg, i.p) produces more analgesic effects in tail immersion test (as a model of acute thermal pain) in comparison with the PCP, PCM and control groups. Meanwhile, this analgesic effect was markedly shown 5-15 min after the compound III application. In formalin test analysis, the acute pain (phase I) could not be affected by any drugs, but the chronic formalin pain (phase II) could be diminished by PCM and especially compound III. The chronic analgesic effect of Methyl-PCM was markedly shown in the late phase of chronic pain.

New morpholine analogues of phencyclidine: chemical synthesis and pain perception in rats.

Phencyclidine (PCP, I) and most its derivatives have demonstrated some pharmacological effects. Accordingly, in this study, the new methoxy (III) and hydroxy-methyl (IV) morpholine PCP derivatives were synthesized. The acute and chronic pain activities of these drugs (III, IV) were investigated by tail immersion and formalin tests on rats and the results were compared with those in PCP, PCM (PCP-morpholine, II), and methyl-PCM (V). Findings indicated that III (6 mg/kg, i.p.) generates more analgesic effects in tail immersion test in comparison with I and II in 20, 40, 45 and 55 min post-injection. These effects were observed in 10, 20, 40, 45 and 50 min after the application of IV (at the same dosage). This analgesic effect was markedly seen in 20, 40, 45 and 50 min after compound IV's application in comparison with the drugs (I-V). In formalin test analysis, the acute chemical pain (Phase I) could not be affected by any drugs (I-V) while chronic formalin pain would be diminished by these new synthesized drugs (III and IV), especially in late Phase II, compared to I and II at the dosage of 6 mg/kg. It is, therefore, concluded that these new synthesized PCP derivates including methoxy-PCM (III) and hydroxy-methyl-PCM (IV) could substantially and respectively diminish acute thermal and chronic chemical pains.

Synthesis and determination of acute and chronic pain activities of 1-[1-(3-methylphenyl) (tetralyl)]piperidine as a new derivative of phencyclidine via tail immersion and formalin tests.

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, CAS 956-90-1, PCP, 1) and ketamine (2-O-chlorophenyl-2-methylaminocyclohexan, CAS 1867-66-9, II) revealed some analgesic effects. Some of their derivatives have been synthesized for biological properties studies. Utilizing 1-tetralone as a starting material, 1-[1-(3-methylphenyl)(tetralyl)]piperidine, (PCP-CH3-tetralyl, III) was synthesized and its analgesic effects were studied on rats via tail immersion (as a model of acute thermal pain) and formalin (as a model of acute chemical and chronic pain) tests and compared with those of ketamine and PCP. The results indicated a marked anti-nociception 2-25 min after ketamine injection, but this analgesic effect lasted for 40 min following PCP-CH3-tetralyl application in the tail immersion test. However, the data obtained from the formalin test showed that chronic pain could be significantly attenuated by ketamine, PCP and PCP-CH3-tetralyl.

Prenatal exposure to phencyclidine produces abnormal behaviour and NMDA receptor expression in postpubertal mice.

Several studies have shown the disruptive effects of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists on neurobehavioural development. Based on the neurodevelopment hypothesis of schizophrenia, there is growing interest in animal models treated with NMDA antagonists at developing stages to investigate the pathogenesis of psychological disturbances in humans. Previous studies have reported that perinatal treatment with phencyclidine (PCP) impairs the development of neuronal systems and induces schizophrenia-like behaviour. However, the adverse effects of prenatal exposure to PCP on behaviour and the function of NMDA receptors are not well understood. This study investigated the long-term effects of prenatal exposure to PCP in mice. The prenatal PCP-treated mice showed hypersensitivity to a low dose of PCP in locomotor activity and impairment of recognition memory in the novel object recognition test at age 7 wk. Meanwhile, the prenatal exposure reduced the phosphorylation of NR1, although it increased the expression of NR1 itself. Furthermore, these behavioural changes were attenuated by atypical antipsychotic treatment. Taken together, prenatal exposure to PCP produced long-lasting behavioural deficits, accompanied by the abnormal expression and dysfunction of NMDA receptors in postpubertal mice. It is worth investigating the influences of disrupted NMDA receptors during the prenatal period on behaviour in later life.

Synthesis and study on analgesic effects of 1-[1-(4-methylphenyl) (cyclohexyl)] 4-piperidinol and 1-[1-(4-methoxyphenyl) (cyclohexyl)] 4-piperidinol as two new phencyclidine derivatives.

Phencyclidine (1-(1-phenylcyclohexyl) piperidine; CAS 956-90-1; PCP, I) has shown analgesic effects. Some of its derivatives have been synthesized and their biological properties have been studied. In this work, new methyl and methoxy hydroxyl derivatives of phencyclidine were synthesized and the analgesic effects of this compounds [(1-[1-(4-methylphenyl) (cyclohexyl)] 4-piperidinol, II), (1-[1-(4-methoxyphenyl) (cyclohexyl)] 4-piperidinol, III)] were studied using tail immersion test on rats and compared to PCP. The results showed that, II can produce more analgesic effects in the tail immersion test (as a model of acute thermal pain) in comparison to the PCP with a marked significant increase in tail immersion latency (15, 40 and 45 min after injection) but for III, only slight analgesic effects (15, 35 and 40 min after injection) was seen (without significant differences between pain thresholds).

Synthesis and evaluation of 1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) analogues as inhibitors of trypanothione reductase.

Thirty two analogues of phencyclidine were synthesised and tested as inhibitors of trypanothione reductase (TryR), a potential drug target in trypanosome and leishmania parasites. The lead compound BTCP (1, 1-(1-benzo[b]thiophen-2-yl-cyclohexyl) piperidine) was found to be a competitive inhibitor of the enzyme (K(i)=1 microM) and biologically active against bloodstream T. brucei (EC(50)=10 microM), but with poor selectivity against mammalian MRC5 cells (EC(50)=29 microM). Analogues with improved enzymatic and biological activity were obtained. The structure-activity relationships of this novel series are discussed.

High specific activity tritiation of TCP and BTCP.

Methods are described to synthesize and characterize tritium labelled TCP and BTCP at high specific activity.

Synthesis with improved yield and study on the analgesic effect of 2-methoxyphencyclidine.

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, CAS 956-90-1, PCP) has shown analgesic effects. Some of its derivatives have been synthesized and their biological properties were studied. Since a methoxy group has been added to the position 2 of the cyclohexane ring of PCP, the resulting compound is more polar than PCP. This compound was synthesized using an improved method with a higher yield. Its analgesic effect was studied using the tail-flick test on rats and was compared with that of ketamine (CAS 1867-66-9). The results showed that 2-methoxyphencyclidine increased tall-flick latencies as compared to the control group. The maximum analgesic effect of the compound occurred 5-10 min after its injection, while the effect of ketamine was observed 10-25 min after injection.

Synthesis and biological properties of 2-hydroxy-1-(1-phenyltetralyl)piperidine and some of its intermediates as derivatives of phencyclidine.

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, CAS 956-90-1, PCP) has shown analgesic effects. Some of its derivatives were synthesized and their biological properties were studied. To date, only saturated ketones have been used as starting materials for synthesizing the phencyclidine family. In order to show desirable biological activity, the aromatic and piperidine rings are necessary for these compounds. Using alpha-tetralone as a starting material, 2-hydroxy-1-(-phenyltetralyl)piperidine, an analogue of the phencyclidine family, and some of its intermediates were synthesized. This ketone was reacted with phenyl magnesium bromide and the resultant alcohol was reacted with acetic anhydride to give alkene that was treated with potassium permanganate to give diol. This compound was treated with a suspension of sodium azide and trichloroacetic acid to give the azide compound that was reduced with LiAlH4 to give the primary amine. Cyclization of this compound with 1,5-dibromopentane finally gave a tertiary amine. It is predicted that the title compound 2-hydroxy-1-(1-phenyltetralyl)piperidine exerts a potent analgesic effect on acute and phasic pain.

Synthesis with improved yield and study on the analgesic effect of 2-hydroxyphencyclidine.

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, CAS 956-90-1, PCP) has shown analgesic effects. Some of its derivatives have been synthesized and their biological properties were studied. Since a hydroxyl group has been added to the position 2 of the cyclohexane ring of PCP, this compound would be more hydrophilic than PCP. This compound was synthesized using a different and improved method with a higher yield. Its analgesic effect was studied using the tail-flick test on rats and was compared with that of ketamine (CAS 1867-66-9). The results showed that 2-hydroxyphencyclidine can increase tail-flick latencies as compared to the control group and indicate that the maximum analgesic effect of this compound occurs 2-5 min after its injection while the effect of ketamine is observed 10-25 min after injection.