In Vitro and In Vivo Pharmaco-Toxicological Characterization of 1-Cyclohexyl-x-methoxybenzene Derivatives in Mice: Comparison with Tramadol and PCP.

1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm.

In Vitro and In Vivo Sequestration of Phencyclidine by Me4 Cucurbit[8]uril*.

We report investigations of the use of cucurbit[8]uril (CB[8]) macrocycles as an antidote to counteract the in vivo biological effects of phencyclidine. We investigate the binding of CB[8] and its derivative Me4 CB[8] toward ten drugs of abuse (3-9, 12-14) by a combination of 1 H NMR spectroscopy and isothermal titration calorimetry in phosphate buffered water. We find that the cavity of CB[8] and Me4 CB[8] are able to encapsulate the 1-amino-1-aryl-cyclohexane ring system of phencyclidine (PCP) and ketamine as well as the morphinan skeleton of morphine and hydromorphone with Kd values ≤50 nm. In vitro cytotoxicity (MTS metabolic and adenylate kinase cell death assays in HEK293 and HEPG2 cells) and in vivo maximum tolerated dose studies (Swiss Webster mice) which were performed for Me4 CB[8] indicated good tolerability. The tightest host⋅guest pair (Me4 CB[8]⋅PCP; Kd =2 nm) was advanced to in vivo efficacy studies. The results of open field tests demonstrate that pretreatment of mice with Me4 CB[8] prevents subsequent hyperlocomotion induction by PCP and also that treatment of animals previously dosed with PCP with Me4 CB[8] significantly reduces the locomotion levels.

DARK Classics in Chemical Neuroscience: Phencyclidine (PCP).

Phencyclidine (PCP, "angel dust", an arylcyclohexylamine) was the first non-natural, man-made illicit drug of abuse, and was coined 'the most dangerous drug in America" in the late 1970s (amidst sensational horror stories of the drug's effects); however, few other illicit drugs have had such a significant and broad impact on society-both good and bad. Originally developed as a new class of anesthetic, PCP-derived psychosis gave way to the PCP hypothesis of schizophrenia (later coined the NMDA receptor hypofunction hypothesis or the glutamate hypothesis of schizophrenia), which continues to drive therapeutic discovery for schizophrenia today. PCP also led to the discovery of ketamine (and a new paradigm for the treatment of major depression), as well as other illicit, designer drugs, such as methoxetamine (MXE) and a new wave of Internet commerce for illicit drugs (sold as research chemicals, or RCs). Furthermore, PCP is a significant contaminant/additive of many illegal drugs sold today, due to its ease of preparation by clandestine chemists. Here, we will review the history, importance, synthesis (both legal and clandestine), pharmacology, drug metabolism, and folklore of PCP, a true DARK classic in chemical neuroscience.

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.

Functional Human α7 Nicotinic Acetylcholine Receptor (nAChR) Generated from Escherichia coli.

Human Cys-loop receptors are important therapeutic targets. High-resolution structures are essential for rational drug design, but only a few are available due to difficulties in obtaining sufficient quantities of protein suitable for structural studies. Although expression of proteins in E. coli offers advantages of high yield, low cost, and fast turnover, this approach has not been thoroughly explored for full-length human Cys-loop receptors because of the conventional wisdom that E. coli lacks the specific chaperones and post-translational modifications potentially required for expression of human Cys-loop receptors. Here we report the successful production of full-length wild type human α7nAChR from E. coli Chemically induced chaperones promote high expression levels of well-folded proteins. The choice of detergents, lipids, and ligands during purification determines the final protein quality. The purified α7nAChR not only forms pentamers as imaged by negative-stain electron microscopy, but also retains pharmacological characteristics of native α7nAChR, including binding to bungarotoxin and positive allosteric modulators specific to α7nAChR. Moreover, the purified α7nAChR injected into Xenopus oocytes can be activated by acetylcholine, choline, and nicotine, inhibited by the channel blockers QX-222 and phencyclidine, and potentiated by the α7nAChR specific modulators PNU-120596 and TQS. The successful generation of functional human α7nAChR from E. coli opens a new avenue for producing mammalian Cys-loop receptors to facilitate structure-based rational drug design.

Phencyclidine Disrupts the Auditory Steady State Response in Rats.

The Auditory Steady-State Response (ASSR) in the electroencephalogram (EEG) is usually reduced in schizophrenia (SZ), particularly to 40 Hz stimulation. The gamma frequency ASSR deficit has been attributed to N-methyl-D-aspartate receptor (NMDAR) hypofunction. We tested whether the NMDAR antagonist, phencyclidine (PCP), produced similar ASSR deficits in rats. EEG was recorded from awake rats via intracranial electrodes overlaying the auditory cortex and at the vertex of the skull. ASSRs to click trains were recorded at 10, 20, 30, 40, 50, and 55 Hz and measured by ASSR Mean Power (MP) and Phase Locking Factor (PLF). In Experiment 1, the effect of different subcutaneous doses of PCP (1.0, 2.5 and 4.0 mg/kg) on the ASSR in 12 rats was assessed. In Experiment 2, ASSRs were compared in PCP treated rats and control rats at baseline, after acute injection (5 mg/kg), following two weeks of subchronic, continuous administration (5 mg/kg/day), and one week after drug cessation. Acute administration of PCP increased PLF and MP at frequencies of stimulation below 50 Hz, and decreased responses at higher frequencies at the auditory cortex site. Acute administration had a less pronounced effect at the vertex site, with a reduction of either PLF or MP observed at frequencies above 20 Hz. Acute effects increased in magnitude with higher doses of PCP. Consistent effects were not observed after subchronic PCP administration. These data indicate that acute administration of PCP, a NMDAR antagonist, produces an increase in ASSR synchrony and power at low frequencies of stimulation and a reduction of high frequency (> 40 Hz) ASSR activity in rats. Subchronic, continuous administration of PCP, on the other hand, has little impact on ASSRs. Thus, while ASSRs are highly sensitive to NMDAR antagonists, their translational utility as a cross-species biomarker for NMDAR hypofunction in SZ and other disorders may be dependent on dose and schedule.

Discovery of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063), a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor.

A novel series of pyridazinone-based phosphodiesterase 10A (PDE10A) inhibitors were synthesized. Our optimization efforts using structure-based drug design (SBDD) techniques on the basis of the X-ray crystal structure of PDE10A in complex with hit compound 1 (IC50 = 23 nM; 110-fold selectivity over other PDEs) led to the identification of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (27h). Compound 27h has potent inhibitory activity (IC50 = 0.30 nM), excellent selectivity (>15000-fold selectivity over other PDEs), and favorable pharmacokinetics, including high brain penetration, in mice. Oral administration of compound 27h to mice elevated striatal 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) levels at 0.3 mg/kg and showed potent suppression of phencyclidine (PCP)-induced hyperlocomotion at a minimum effective dose (MED) of 0.3 mg/kg. Compound 27h (TAK-063) is currently being evaluated in clinical trials for the treatment of schizophrenia.

From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs.

PCP or phencyclidine was discovered in 1956 and soon became a popular street drug. Dissociatives including PCP, ketamine, and dextromethorphan have been used non-medically for their mind-altering effects for over 60 years. Many of these compounds have also been used clinically and in legitimate research. At least 14 derivatives of PCP were sold for non-medical and illict use from the late 1960s until the 1990s. With the advent of the Internet, the drug market underwent a dramatic evolution. While initially gray-market chemical vendors offering dextromethorphan and ketamine thrived, most recently the market has shifted to legal high and online-based research chemical vendors. Starting with the first dissociative research chemical, 4-MeO-PCP in 2008, the dissociative research chemical market has rapidly evolved and currently comprises at least 12 dissociatives, almost half of which were unknown in the scientific literature prior to their introduction. Several of these, including methoxetamine, have reached widespread use internationally. A historical account of non-medical use of over 30 dissociative compounds was compiled from a diverse collection of sources. The first complete portrait of this underground market is presented along with the relevant legal, technological, and scientific developments which have driven its evolution.

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.

The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor.

In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)-2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.

Effect of phencyclidine derivatives on anxiety-like behavior using an elevated-plus maze test in mice.

OBJECTIVES: The study attempted to investigate the anti-anxiety activities of Phencyclidine (1-(1-phenylcyclohexyl) piperidine, PCP, I) and some of its derivatives (M, F, L, B, S, P) with the elevated-plus maze (EPM) Test. MATERIAL AND METHODS: Phencyclidine and its derivatives (M, F, L, B, S, P) were administrated intraperitoneally (i.p.) at a dose of 10 mg/kg to male mice. Anxiety-like behaviors were assessed using the elevated-plus maze test. RESULTS: EPM results revealed an increase in open arms time spent after applying PCP and M, L, P, and B compounds at the administered dosage. Moreover, an increase in the number of open arm entries was observed with M, P, and B compounds. The P, B and S compounds increased the locomotion of animals, too, which might be considered as the side effect to the compounds. CONCLUSIONS: Considering the elevated-plus maze results, it was concluded that M and L compounds could be considered as a potential anxiolytic with less side effects due to a probable high electron donation of the methoxy group, as well as the hydrophilic properties of hydroxyl groups on these compounds.

Designer drugs: a medicinal chemistry perspective.

There are numerous medicinal chemistry reports in the literature describing the pharmacological properties of thousands of narcotics, stimulants, hallucinogens, sedative-hypnotic drugs, cannabinoids, and other psychoactive substances as well as synthetic methods for their preparations. This information, while essential for the advancement of science, has been used by clandestine chemists to manufacture and market an endless variety of analogs of so-called designer drugs. In this review, we describe how clandestine chemists used the principles of medicinal chemistry to design molecules, referred to as designer drugs, that elicit the effects of opioids, amphetamine and analogs, cannabinoids, and phencyclidine analogs while circumventing the law.

Synthesis and analgesic effects of 1-[1-(2-methylphenyl)(cyclohexyl)]-3-piperidinol as a new derivative of phencyclidine in mice.

Phencyclidine (1-(1-phenylcyclohexyl) piperidine, CAS 956-90-1, PCP, I) and its derivatives have shown many analgesic effects. In this research, a new derivative of PCP (1-[1-(2-methylphenyl) (cyclohexyl)l3-piperidinol, PD, II) was synthesized and its analgesic (acute and chronic pains) effects were examined on rats 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 are compared to PCP and control groups. The results indicated that II produces higher analgesic effects in the tail immersion test compared to the PCP and control groups, with a marked and significant increase in tail immersion latency for the doses 1, 5 and 10 mg/kg. The formalin test showed that PD (II) is not effective in acute chemical pain (phase I, 0-5 min after injection) in all doses but chronic pain (initial-phase II, 15-40 min after injection) is significantly attenuated by this compound compared to PCP and saline (control) in dosesof 5 and 10 mg/kg. It is concluded that II is effective in acute thermal (in all doses) and chronic (doses of 5 and 10 mg/kg) pains; however, it is not effective in acute chemical pain compared to PCP and control.

Chemistry, pharmacology, and metabolism of emerging drugs of abuse.

In recent years, besides the classic designer drugs of the amphetamine type, a series of new drug classes appeared on the illicit drugs market. The chemistry, pharmacology, toxicology, metabolism, and toxicokinetics is discussed of 2,5-dimethoxy amphetamines, 2,5-dimethoxy phenethylamines, beta-keto-amphetamines, phencyclidine derivatives as well as of herbal drugs, ie, Kratom. They have gained popularity and notoriety as rave drugs. The metabolic pathways, the involvement of cytochrome P450 isoenzymes in the main pathways, and their roles in hepatic clearance are also summarized.

1,2-ethane bis-1-amino-4-benzamidine is active against several brain insult and seizure challenges through anti-NMDA mechanisms targeting the 3H-TCP binding site and antioxidant action.

Five bis-benzamidines were screened towards murine magnesium deficiency-dependent audiogenic seizures, unravelling two compounds with efficacious doses 50 (ED(50)) less than 10mg/kg. They were also screened against maximal electroshock and subcutaneous pentylenetetrazole-induced seizures, and explored for superoxide -scavenging activity. 1,2-Ethane bis-1-amino-4-benzamidine (EBAB) was selected and evaluated in 6 Hz seizure test (ED(50)=49 mg/kg) and at 4 microg/kg in focal cerebral ibotenate poisoning in pups (sizes of both white and grey matter wounds were halved). EBAB was further tested on NMDA-induced seizures in mice (ED(50)=6 mg/kg) and on (3)H-TC -binding to a rodent cerebral preparation (IC(50)=1.4 microM). Taken as a whole, present data emphasise the suitability of bis-benzamidines as templates for designing brain protective compounds.

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.

Effects of trihexyphenydil, the structural analog of phencyclidine, on neocortical and hippocampal electrical activity in sleep-waking cycle.

Finding about structural and functional relation between NMDA receptors specific binding and phencyclidine sites was very important for a possible modulation of NMDA receptors' function. We have therefore got interested what would happen with EEG and vegetative patterns of PS in the case when NMDA receptors function is modulated by blocking of phencyclidines' site. Consequently, we studied the effects of Trihexyphenydil, the structural analog of phencyclidine, on neocortical and hippocampal electrical activity in SWC. On cats (n=5) metallic electrodes were implanted under Nembutal anesthesia. EEG registration lasting 12 hr daily started after animals' recovery. Trihexyphenydil was administered intraperitoneally (0.5 mg/kg - 1 mg/kg). Statistical processing was made by Students' t-test. Trihexyphenydil resulted in dissociated triggering of PS. Rapid eye movements and PGO waves appeared on the face of active waking state. Therefore on the background of behavioral active waking according to electrical activity of the visual cortex and rapid eye movements, electrographic patterns of paradoxical sleep were recorded. Thus in our experiments it was shown firstly that the mechanism of hallucinogenic action of Trihexyphenydil is closely related to the disturbance of paradoxical sleep integrity. Blocking of NMDA receptors phencyclidines site and therefore functional modulation of these receptors produce the splitting of PS patterns and their intrusion in waking state. Such an effect never takes place in normal conditions since the waking system has the powerful inhibitory influence on the PS triggering system. Suggestion is make that NMDA glutamate receptors must be involved in mechanisms providing structural and functional integrity of PS and that fulfillment of such function is possible in the case when the NMDA receptors phencyclidine site isn't in blocked state. Normal functioning of NMDA receptors phencyclidine site represents the mechanism which inhibits and/or hampers appearance of hallucination. NMDA glutamate receptors, possessing phencyclidine site, are implicated in the mechanisms providing structural and functional integrity of PS.

The 'wired' universe of organic chemistry.

The millions of reactions performed and compounds synthesized by organic chemists over the past two centuries connect to form a network larger than the metabolic networks of higher organisms and rivalling the complexity of the World Wide Web. Despite its apparent randomness, the network of chemistry has a well-defined, modular architecture. The network evolves in time according to trends that have not changed since the inception of the discipline, and thus project into chemistry's future. Analysis of organic chemistry using the tools of network theory enables the identification of most 'central' organic molecules, and for the prediction of which and how many molecules will be made in the future. Statistical analyses based on network connectivity are useful in optimizing parallel syntheses, in estimating chemical reactivity, and more.