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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.

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 Me 4 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 Me 4 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 K d 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 Me 4 CB[8] indicated good tolerability. The tightest host⋅guest pair (Me 4 CB[8]⋅PCP; K d =2 nm) was advanced to in vivo efficacy studies. The results of open field tests demonstrate that pretreatment of mice with Me 4 CB[8] prevents subsequent hyperlocomotion induction by PCP and also that treatment of animals previously dosed with PCP with Me 4 CB[8] significantly reduces the locomotion levels., (© 2020 Wiley-VCH GmbH.)

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.

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.

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., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

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.

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.

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., (Copyright © 2014 John Wiley & Sons, Ltd.)

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.

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.

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.

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., (© 2012 New York Academy of Sciences.)

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.

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., (Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.)

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.

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.

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.

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.

Studies are described on the metabolism and the toxicological detection of the phencyclidine-derived designer drugs N-(1-phenylcyclohexyl)-2-ethoxyethanamine (PCEEA) and N-(1-phenylcyclohexyl)-2-methoxyethanamine (PCMEA) in rat urine using gas chromatographic/mass spectrometric (GC/MS) techniques. The identified metabolites indicated that PCEEA and PCMEA were transformed to the same metabolites by N-dealkylation and O-dealkylation partially followed by oxidation of the resulting alcohol to the respective carboxylic acid and hydroxylation of the cyclohexyl ring at different positions and combinations of those. Finally, aromatic hydroxylation of the O-dealkylated metabolites was partially followed by hydroxylation of the cyclohexyl ring at different positions. All metabolites were partially excreted in conjugated form. The authors' systematic toxicological analysis (STA) procedure using full-scan GC/MS after acid hydrolysis, liquid-liquid extraction and microwave-assisted acetylation allowed the detection of an intake of a common drug users' dose both of PCEEA and PCMEA in rat urine. Assuming similar metabolism in humans, the STA should be suitable for proof of an intake of PCEEA and PCMEA in human urine, although their differentiation is not possible due to common metabolites., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

The use of selective chemical inhibitors of human cytochrome P450 (P450) enzymes represents a powerful method by which the relative contributions of various human P450 enzymes to the metabolism of drugs can be determined. However, the identification of CYP2B6 in the metabolism of drugs has been more challenging because of the lack of a well established inhibitor of this enzyme. In this report, we describe the selectivity of 2-phenyl-2-(1-piperidinyl)propane (PPP) as an inactivator of CYP2B6 and compare this selectivity versus other CYP2B6 inactivators: 1,1',1''-phosphinothioylidynetrisaziridine (thioTEPA), clopidogrel, and ticlopidine. Values of K(I) and k(inact) for PPP were 5.6 microM and 0.13/min for bupropion hydroxylase catalyzed by pooled human liver microsomes, and values for thioTEPA were similar (4.8 microM and 0.20/min, respectively). Intrinsic inactivation capability was considerably greater for clopidogrel because of a greater k(inact) value (1.9/min). Ticlopidine was potent with K(I) and k(inact) values of 0.32 microM and 0.43/min, respectively. The selectivity of these four agents for CYP2B6 was determined by testing their effects on other human P450 enzyme activities using conditions that yield approximately 90% inactivation of CYP2B6 activity. The results showed that preincubation of human liver microsomes with PPP at 30 microM for 30 min provided more selective inhibition for CYP2B6 than thioTEPA, clopidogrel, and ticlopidine. Furthermore, the use of clopidogrel is complicated by the observation that this agent is not stable in the presence of human liver microsomes, even without addition of NADPH. Therefore, PPP can serve as a selective chemical inactivator of CYP2B6 and be used to define the role of CYP2B6 in the metabolism of drugs.

Human cytochrome P450 (P450) 2B6 plays an important role in the metabolism of many drugs used in the clinic, and it has been shown to be highly polymorphic and inducible by a variety of substrates. The metabolism of phencyclidine (PCP) by P450 2B6 results in mechanism-based inactivation of the enzyme. We investigated the effects of a naturally occurring mutation of P450 2B6 where a lysine 262 is changed to an arginine (K262R) on PCP metabolism and mechanism-based inactivation of 2B6 by PCP. The K262R mutant retained the 7-ethoxy-4-trifluoromethylcoumarin O-deethylation activity when it was incubated with PCP and NADPH in the reconstituted system, whereas the wild-type enzyme was readily inactivated by PCP. Spectral binding studies showed that PCP was reversibly bound in the active site of the K262R mutant with slightly higher affinity (156 muM) compared with the wild-type 2B6 (397 muM). In addition, all the metabolites of PCP (M1-M8) that were formed by the wild-type enzyme were also formed by the K262R mutant. Although the K262R mutant metabolized PCP to give similar metabolite profiles, the overall rate of metabolite formation was lower than the wild-type enzyme. A reactive intermediate of PCP was formed by wild-type P450 2B6 and trapped with glutathione (GSH). However, no GSH conjugates were detected from incubations with the K262R mutant. These data suggest that the lysine 262 residue plays an important role in the formation of a reactive intermediate of PCP that leads to the mechanism-based inactivation of P450 2B6.

This is a report of postmortem false-positive reactivity using an enzyme-multiplied urine phencyclidine (PCP) immunoassay (EMIT II+) due to a single-agent fatal tramadol overdose. An autopsy of a 42-year-old male who died alone at home revealed no identifiable lethal anatomic abnormalities, thus leading to toxicologic analysis. Femoral blood was obtained for drug testing by high-performance liquid chromatography (HPLC) and showed a tramadol level of 14.0 mg/L, 2 orders of magnitude greater than the therapeutic range (0.1 to 0.3 mg/L). Urine was also obtained and EMIT II+ immunoassay revealed positivity for PCP at 88 mAU/min. However, confirmatory testing by HPLC failed to identify PCP in either the urine or serum. To verify the suspicion that this was a false-positive PCP result, stock solutions of tramadol and its major metabolite (O-desmethyltramadol) at concentrations of 100 mg/L in 10% methanol/H2O were compared with a blank solution (10% methanol/H2O) for EMIT II+ PCP reactivity and demonstrated reactivities of 44 mAU/min and 27 mAU/min, respectively. While these individual results were below the cutoff reactivity for a positive EMIT II+ PCP result (ca. 85 mAU/min), they were much more reactive than the blank calibrator (set at 0 mAU/min). Therefore, we conclude that the immunoreactivity of tramadol and its metabolites in aggregate is responsible for the PCP immunoassay interference and false-positive result.

The mechanism behind the observed inactivation of human P450 2B6 by phencyclidine (PCP) has been evaluated over the past 2 decades. The scope of the current investigation was to contribute to the fundamental knowledge of PCP oxidation and perhaps the mechanism behind P450 inactivation. To study the chemistry of PCP oxidation, we subjected PCP to the Fenton reagent. Under Fenton chemistry conditions, oxidation on all three PCP rings was observed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). When PCP was incubated with the Fenton system in the presence of glutathione (GSH), three GSH-PCP conjugates were identified. Subsequent LC-MS/MS analysis of these conjugates revealed two species that had GSH attached to the cyclohexane ring of PCP and a third conjugate in which GSH was adducted to the piperidine ring. When PCP was incubated across a panel of P450 enzymes, several enzymes, including P450s 2D6 and 3A4, were able to catalyze the formation of the PCP iminium ion, whereas P450s 2B6 and 2C19 were exclusively able to hydroxylate secondary carbons on the cyclohexane ring of PCP. Subsequent mechanistic experiments revealed that only P450s 2B6 and 2C19 demonstrated loss of catalytic activity after preincubation with 10 microM PCP. Finally, investigation of P450 2B6 inactivation using structural analogs of PCP revealed that blocking the para-carbon atom on the cyclohexane ring of PCP from oxidation protected the P450 2B6 from inactivation, which suggests that a reactive intermediate generated during the hydroxylation of the cyclohexane ring may be linked to the mechanism of inactivation of P450 2B6 by PCP.

We investigated the molecular mechanisms and the binding site location for the fluorophor crystal violet (CrV), a noncompetitive antagonist of the nicotinic acetylcholine receptor (AChR). To this end, radiolabeled competition binding, fluorescence spectroscopy, Schild-type analysis, patch-clamp recordings, and molecular dynamics approaches were used. The results indicate that (i) CrV interacts with the desensitized Torpedo AChR with higher affinity than with the resting state at several temperatures (5-37 degrees C); (ii) CrV-induced inhibition of the phencyclidine (PCP) analogue [(3)H]thienylcyclohexylpiperidine binding to the desensitized or resting AChR is mediated by a steric mechanism; (iii) tetracaine inhibits CrV binding to the resting AChR, probably by a steric mechanism; (iv) barbiturates modulate CrV binding to the resting AChR by an allosteric mechanism; (v) CrV itself induces AChR desensitization; (vi) CrV decreases the peak of macroscopic currents by acting on the resting AChR but without affecting the desensitization rate from the open state; and (vii) two tertiary amino groups from CrV may bind to the alpha1-Glu(262) residues (located at position 20') in the resting state. We conclude that the CrV binding site overlaps the PCP locus in the resting and desensitized state. The noncompetitive action of CrV may be explained by an allosteric mechanism in which the binding of CrV to the extracellular mouth of the resting receptor leads to an inhibition of channel opening. Binding of CrV probably increases desensitization of the resting channel and stabilizes the desensitized state.

Background: For the first time in ten years, phencyclidine (PCP) has been confiscated in Norway. Physicians should be aware of this substance when treating intoxications., Methods: Relevant literature was identified by search in Medline. This review presents the pharmacological properties and effects of phencyclidine as well as symptoms and treatment of phencyclidine intoxication., Results and Interpretation: Phencyclidine exhibits hallucinogenic, depressant and stimulant properties. Phencyclidine interacts as an antagonist to the N-methyl-D-aspartate (NMDA) receptor in the central nervous system. Severe NMDA receptor hypofunction can elicit clinical symptoms similar to a schizophrenic episode.

Four affinity chromatography stationary phases have been developed based upon immobilized nicotinic acetylcholine receptor (nAChR) subtypes, the alpha3beta2, alpha3beta4, alpha4beta2, and alpha4beta4 nAChRs. The stationary phases were created using membranes from cell lines expressing the subtypes and an immobilized artificial membrane stationary phase. The immobilized nAChRs were characterized using frontal chromatography with the agonist epibatidine as the marker. The observed binding affinities for the agonists epibatidine, nicotine, and cytisine were consistent with reported values, indicating that the nAChRs retained their ability to bind agonists. The noncompetitive inhibitors (NCIs) of the nAChR (R)- and (S)-mecamylamine, phencylcidine, dextromethoprphan, and levomethorphan were also chromatographed on the columns using nonlinear chromatography techniques. The studies were carried out before and after exposure of the columns to epibatidine. The NCI retention times increased after exposure to epibtatidine as did the enantioselective separation of mecamylamine and methorphan. The results indicate that the immobilized nAChRs retained their ability to undergo agonist-induced conformational change from the resting to the desensitized states. The columns provide a unique ability to study the interactions of NCIs with both of these conformational states.

Several adamantyl derivatives of thienyl phencyclidine (tenocyclidine; TCP) were newly sythesized and characterized: adamantyl derivatives containing piperidine (TAPIP), pyrrolidine (TAPYR), and morpholine (TAMORPH) groups. Their biological activity was evaluated by in vitro testing of their effect on the proliferative and reproductive ability (cytotoxicity) of a human tumor cell strain and nonmalignant mouse fibroblasts in culture. We also tested them for their radioprotective effect after ionizing irradiation, and as anticancer agents on the same human tumor cell strain. Compared with TCP, adamantyl derivatives are less toxic and have outstanding radioprotective properties. These derivatives (especially TAMORPH) increase apoptotic death of human malignant cells. The radiation-modifying effect studied on C3Hf mice in vivo showed that the adamantyl derivatives of TCP have a more enhanced radioprotective effect and that they are less toxic than TCP itself. The present data are discussed and compared with those previously reported for structurally related phencyclidine derivatives.

Open channel blockers of NMDA receptors interact with the channel gate in different ways. Compounds like MK-801 and phencyclidine exhibit pronounced trapping block, whereas 9-aminoacridine and tetrapentylammonium cannot be trapped. Some blockers such as memantine and amantadine exhibit intermediate properties, so called 'partial trapping'. To analyze the determinants of trapping we have synthesized a series of mono- and dicationic derivatives of phenylcyclohexyl. The blocking action of these compounds as well as that of amantadine has been studied on native NMDA receptors of hippocampal pyramidal neurons. Use-dependence and kinetics of the blockade have been analyzed to estimate the degree of trapping. Dimensions of the blocking molecules apparently do not correlate with their trapping. However, the degree of trapping is voltage-dependent and correlates with the kinetics of unblock. For instance, amantadine behaved as non-trapping blocker at positive voltages, but demonstrated significant trapping at negative voltages. The data may be explained by the model in which the NMDA receptor channel has two binding sites: the shallow and deep ones. Binding to the deep but not to the shallow site allows trapping of the blockers.

We used a series of adamantane derivatives to probe the structure of the phencyclidine locus in either the resting or desensitized state of the nicotinic acetylcholine receptor (AChR). Competitive radioligand binding and photolabeling experiments using well-characterized noncompetitive antagonists such as the phencyclidine analogue [piperidyl-3,4-(3)H(N)]-N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine ([(3)H]TCP), [(3)H]ethidium, [(3)H]tetracaine, [(14)C]amobarbital, and 3-(trifluoromethyl)-3-(m-[(125)I]iodophenyl)diazirine ([(125)I]TID) were performed. Thermodynamic and structure-function relationship analyses yielded the following results. (1) There is a good structure-function relationship for adamantane amino derivatives inhibiting [(3)H]TCP or [(3)H]tetracaine binding to the resting AChR. (2) Since the same derivatives inhibit neither [(14)C]amobarbital binding nor [(125)I]TID photoincorporation, we conclude that these positively charged molecules preferably bind to the TCP locus, perhaps interacting with alphaGlu(262) residues at position M2-20. (3) The opposite is true for the neutral molecule adamantane, which prefers the TID (or barbiturate) locus instead of the TCP site. (4) The TID site is smaller and more hydrophobic (it accommodates neutral molecules with a maximal volume of 333 +/- 45 A(3)) than the TCP locus, which has room for positively charged molecules with volumes as large as 461 A(3) (e.g., crystal violet). This supports the concept that the resting ion channel is tapering from the extracellular mouth to the middle portion. (5) Finally, although both the hydrophobic environment and the size of the TCP site are practically the same in both states, there is a more obvious cutoff in the desensitized state than in the resting state, suggesting that the desensitization process constrains the TCP locus. A plausible location of neutral and charged adamantane derivatives is shown in a model of the resting ion channel.

Since the three-dimensional structure of the NMDA receptor has not been determined experimentally, indirect computer-assisted molecular modeling techniques appear to be of great usefulness in the characterization of the common pharmacophore of all NMDA receptor noncompetitive antagonists, despite their structural differences. Indeed, the conformational analysis of three different chemical families (MK801, PCP, dexoxadrol and their analogues), has allowed us to visualize the different conformations and configurations of each molecule. Superimposition with configurations 1 and 2 of the MK801 molecule has allowed us to propose active conformations and thereafter a geometrical characterization of the pharmacophore, especially the determination of the orientation of the nitrogen lone pair (NLP) related to the phenyl. On the other hand, electrostatic studies, combined with geometrical features, have allowed us to schematize the interaction mode of an active conformation to the binding site. Finally, studies of the molecular lipophilic potential (MLP) have provided us information on the position of lipophilic and hydrophilic zones of the pharmacophore.

Molecular mechanics calculations using MM3-92 and ab initio quantum mechanical calculations using SPARTAN 5.0 were performed on the structurally similar PCP and BTCP, in which only the latter has a cocaine-like pharmacological profile as a dopamine reuptake blocker. Calculations were also performed on BTCP analogs with a methyl group in various positions of the cyclohexane ring. The results for the cis-2-methyl compound, which retains good pharmacological activity, allowed us to determine that an aryl-axial conformer is the biologically active form for at least some of the compounds in this series. However, an aryl-equatorial conformer presents the identical pharmacophore, as shown by superposition of the two conformers. X-ray crystallographic structures were also obtained for BTCP and related compounds with a 2-methyl group on the cyclohexane ring, with reasonable agreement between the computational and experimental results. Superposition studies were performed with two rigid analogs of cocaine which illustrate the optimal orientations of the ammonium hydrogen for monoamine transporters. There is excellent agreement between a 'back-bridged' cocaine analog that is optimal as a dopamine reuptake blocker and the previously proposed biologically active conformer of methylphenidate. However, BTCP is found to be a better fit to the 'front-bridged' cocaine analog that is optimal for a serotonin reuptake blocker.

This study discusses the potential exposure of occupational workers and general consumers in the European Union (EU) to polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) caused by exposure to pentachlorophenol (PCP) and its derivatives. A synthesis of reported exposure data relating exposure to PCP and its derivatives in an occupational setting has indicated that the PCDD/F intake for exposure in the 1990s averaged over a lifetime is likely to be in the order of 0.02-1 pg I-TEQ kg-1 bw day-1 with actual exposures more likely to occur at the lower end of the range, around the median of 0.16 pg I-TEQ kg-1 bw day-1. Workers who have experienced past exposure to PCP and its derivatives especially in the early to mid 1980s, will have been subjected to higher exposures to PCDD/Fs due to the generally higher concentrations of PCDD/Fs in PCP products at that time. Exposure to PCP and its derivatives via the food chain is judged to be the most significant intake route of PCDD/Fs into consumers. The ingestion of milk and dairy products obtained from cows grazed on pasture dressed with sewage sludge has the potential to raise the average daily intake of PCDD/Fs via the diet by about 40% if all foods consumed derived from sludge amended soil. To the extent quantifiable, exposure to PCP in an occupational setting contributed approximately 16% as a median to the overall background exposure to PCDD/Fs, while for consumers this contribution ranged from 2 to 60% depending on the exposure to sludge amended foods.

The crystal structure of monoclonal antibody (mAb) 6B5 Fab fragment complexed with 1-(1-phenylcyclohexyl)piperidine (PCP or phencyclidine) was determined at 2.2-A resolution. 6B5 was originally produced from a mouse immunized with a phencyclidine analogue hapten 5-[N-(1'phenylcyclohexyl)amino]pentanoic acid conjugated to bovine serum albumin. This mAb was selected for further study because of its high affinity (Kd = 2 x 10(-9) M/liter) for PCP and usefulness in reversing PCP-induced central nervous system toxicity in laboratory animals. The dominant feature of the 6B5 Fab.PCP complex is the deep binding site and hydrophobic nature of the interaction. The ligand binding pocket of 6B5 Fab has numerous aromatic side chains, as compared with other known Fab structures. The most notable feature of the binding site is a Trp at position 97H (H-chain), and the side chain of this residue appears to act as a hydrophobic umbrella on the ligand in the antigen binding pocket. There are only two other known Fabs found with a Trp at the 97H position in complementarity determining region (CDR) H3, but they do not play a major role in the interaction with their respective antigens; in both Fab TE33 and R6.5 the Trp 97H side chain is positioned away from the bound antigen. Comparison of the CDR residues of 6B5 with other Fab structures with similar CDR sizes and amino acid compositions reveals a number of important patterns of residue substitutions that appear to be critical for specific PCP ligand interactions.

Three phencyclidine (PCP) analogues possessing a highly rigid carbocyclic structure and an attached piperidine ring which is free to rotate were synthesized. Each analogue has a specific fixed orientation of the ammonium center of the piperidinium ring to the centrum of the phenyl ring. The binding affinities of the rigid analogues 1-piperidino-7,8-benzobicyclo[4.2.0]octene (14), 1-piperidinobenzobicyclo[2.2.1]heptene (16), and 1-piperidinobenzobicyclo[2.2.2]octene (13) for the PCP receptor ([3H]TCP) and th-receptor (NANM) were determined. The three analogues show low to no affinity for the PCP receptor but good affinity for the th-receptor and can be considered th-receptor selective ligands with PCP/th ratios of 13, 293, and 368, respectively. The binding affinities for the th-receptor are rationalized in terms of a model for the th-pharmacophore.

A sensitive gas chromatographic assay using mass selective-detection has been developed for the simultaneous quantitation of the enantiomers of (+/-)-gacyclidine (a non competitive N-methyl-D-aspartate antagonist) in human plasma. Gacyclidine enantiomers and phencyclidine (PCP), the internal standard, were extracted using a single-step liquid-liquid extraction with hexane at pH 8.0. Each enantiomer was separated on a chiral gas chromatography capillary column and specifically detected by mass spectrometry (MS) in selected-ion monitoring (SIM) mode. Gacyclidine enantiomers and PCP were monitored using the fragment ions at m/z 206 and 200, respectively. No interference was observed from endogenous components. The limit of quantitation (LOQ) for each enantiomer of gacyclidine was 300 pg/ml by using plasma samples of 500 microl. The calibration curves were linear (r2=0.998) over a range of 0.3125 to 20 ng/ml. The extraction efficiency was higher than 95% for both enantiomers. Intra- and inter-day bias were less than 10% at every standard curve concentration. Intra-day precision was less than 19% for (-)-gacyclidine and 15% for (+)-gacyclidine. Inter-day precision was below 15% for both enantiomers. The assay was validated for an enantioselective pharmacokinetic study in healthy male volunteers.

A series of permanently charged benzo[b]quinolizinium cations having lower lipophilicity than MK-801 or phencyclidine (PCP) were synthesized. Data relating agonist independent block of N-methyl-D-aspartic acid (NMDA) ion channels to log D are described. Closed channel access is predicted to result in a more noncompetitive profile of antagonism compared to selective open channel blockers, which are uncompetitive inhibitors. Reduced closed channel block may underlie the absence of PCP or MK-801-like behavioral side effects observed for benzo[b]-quinolizinium cations.

We previously reported (J. Med. Chem. 1993, 36, 1188-1193) that changes to the ring size of the piperidine and cyclohexyl rings of the high-affinity and selective dopamine (DA)-uptake inhibitor 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine (BTCP, 2) caused different, and in some cases opposite, changes in affinity for sites on the DA transporter labeled by [3H]BTCP and [3H]-cocaine. These results suggested that the radioligands label different sites on the transporter. In the present study, we extend the structure-activity relationships (SAR) of BTCP by studying the binding characteristics of a series of N,N-disubstituted 1-(2-benzo[b]thienyl)cyclohexylamines 7-32 at the DA transporter. Cyclohexyl was selected as opposed to other ring sizes since it corresponds to BTCP. The binding results indicate that a considerable degree of structural variation is permitted for the N-substituents, while still retaining nanomolar affinity for sites on the transporter (studied in rat forebrain homogenates). As observed in our earlier study, the differential effects of structural change on binding to sites on the DA transporter labeled by these radioligands suggests that they are different and distinct binding sites. In general, and up to a point, increasing the size and lipophilicity of the N substituents resulted in improvements in binding but appeared to have less predictable effects on DA-uptake inhibition (as measured in rat brain synaptosomes). The binding of these compounds to sites labeled by [3H]BTCP appeared to correlate best with IC50 for DA-uptake inhibition. To our surprise, the monoalkyl N-substituted BTCP derivatives displayed the highest affinity for the DA transporter of all the compounds in this series. For example, the N-(cyclopropylmethyl) derivative 14 displayed IC50's = 23 nM ([3H]cocaine) and 1 nM ([3H]-BTCP), and the N-butyl derivative 10 showed IC50's = 60 nM ([3H]cocaine) and 0.3 nM ([3H]-BTCP). BTCP exhibited IC50's of 39 nM ([3H]cocaine) and 5 nM ([3H]BTCP) in this assay. The observation that N,N-dibutyl derivative 31 exhibited low ratios of IC50 [3H]cocaine/IC50 DA reuptake and IC50 [3H]BTCP/IC50 DA reuptake suggests that it may be a potential candidate for cocaine antagonism studies. The effect of additional amino, amide, and aromatic groups on the N-substituents was examined, and the results are discussed. The failure of all of the compounds in this series to bind phenycyclidine receptors coupled with their high affinity and range of selectivities at the DA transporter identifies many of them as useful tools for probing the mode of action of BTCP at this site.

A review of the synthetic routes to phencyclidine (PCP, 1-(1-phenylcyclohexyl)piperidine) available in the open literature is presented. The emphasis herein is directed toward the forensic investigation of clandestine PCP laboratories. Six published synthetic routes to PCP/analogs are discussed. Each method is rated for overall yield, degree of difficulty and potential hazard, in order to assist the forensic chemist in evaluation of a particular clandestine operation. One clandestine recipe is illustrated and discussed.

The quantitative structure-activity relationships (QSAR's) of 3 series of arylcyclohexylamines have been investigated using computational chemistry and multivariate statistics. Principal component analysis of the aromatic ring data set demonstrated some clustering of activity categories. Biological activity of the cyclohexane ring data set was correlated with molar refractivity. These findings may be useful for predicting the activity of novel neuroprotective agents.

Piperidine and cyclohexyl ring homologues of the high-affinity dopamine (DA) uptake inhibitor 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine (BTCP, 3) were each prepared in four steps from the appropriate cycloalkanones. These compounds were tested for their ability to displace [3H]BTCP and [3H]cocaine and to inhibit [3H]DA uptake in rat striatal homogenates. The ratios IC50([3H]cocaine)/IC50([3H]BTCP) ranged from 62 for BTCP to 1.5 for 1-[2-(benzo[b]thienyl)-cyclopentylamine (17); cocaine gave a ratio of 0.6. This indicates that BTCP is the most selective of all the compounds tested for sites labeled by [3H]BTCP whereas cocaine is most selective for sites labeled by [3H]cocaine. The wide differences in the relative abilities of these compounds to displace [3H]BTCP and [3H]cocaine suggests that these two radioligands are labeling different sites on the transporter. In general, the compounds structurally related to BTCP exhibited greater selectivity for sites labeled by [3H]BTCP. However, several of the BTCP-related derivatives showed greater (compared with BTCP and cocaine) ability to displace [3H]cocaine. Most notably, 1-[1-(2-benzo[b]thienyl)cyclohexyl]pyrrolidine (7) exhibited a 3.4-fold greater affinity for these sites compared with BTCP and a 9-fold greater affinity at these sites than cocaine. Most of the BTCP homologues displayed greater ability to inhibit [3H]DA uptake in rat forebrain synaptosomes than cocaine. BTCP and 7 were the most potent of all the compounds tested in terms of their ability to inhibit uptake of [3H]DA. IC50 ratios for [3H]cocaine binding/[3H]DA uptake ranged from 0.47 for 1-[1-(2-benzo[b]thienyl)cyclopentyl]homopiperidine (11) to 8.8 for 1-(2-benzo[b]thienyl)cyclohexylamine (4). The importance of this ratio remains unclear in terms of identification of potential cocaine antagonists. As for BTCP, all of the compounds tested showed Ki values > 10,000 nM for displacement of [3H]TCP from rat brain homogenates. These compounds were able to displace the highly selective sigma receptor probe [3H]-(+)-pentazocine from guinea pig brain homogenates with Ki values ranging from 125 to 9170 nM. The significance of their sigma-binding activity in light of their dopaminergic properties is unclear. The diverse binding properties of these compounds at the DA-uptake site and their spectrum of inhibitory activities for [3H]DA uptake identifies them as a useful base for the development of subtype selective probes at this site. These compounds will allow further study of the structure and function of the "cocaine" receptor as well as the development of potential cocaine antagonists.

The phencyclidine analogues (+/-)-alpha-, (+/-)-beta-, and (+)-alpha- and and (-)-alpha-4-hydroxy-3-methyl-4-phenyl-1-(1-phenylcyclohexyl)piperidine, all with known relative and absolute stereochemistry, have been prepared, and their analgesic potencies related to corresponding prodines. In contrast to the prodines, the (+/-)-alpha-phencyclidine analogue was a more potent analgesic than its diastereoisomer, while in agreement with observations in the prodine series, the 3R,4S-alpha-enantiomer displayed substantially greater potency than its mirror image form.

The (-)- and (+)-isomers of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines have been synthesized and the achiral cis- and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines were prepared, and their in vitro [displacement of [3H]TCP (1-[1-(2-thienylcyclohexyl)]piperidine) from the PCP (1-(1-phenylcyclohexyl)piperidine) binding site] and in vivo (rotarod assay) activities determined. The 1-(1-phenyl-2-methylcyclohexyl)piperidine isomers were resolved by classical crystallization procedures, through the diastereomeric salts obtained with d- and l-10-camphorsulfonic acid. The relative stereochemistry of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines and the achiral cis- and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines was established by using 13C and 1H NMR. Both (-)-trans-1-(1-phenyl-2-methylcyclohexyl)piperidine ((-)-2) and (+)-trans-1-(1-phenyl-2-methylcyclohexyl)piperidine ((+)-2) were examined by single-crystal X-ray analysis, and the absolute configuration of (-)-2 was determined to be 1S,2R. The (-)-2 was found to be about five times more potent than PCP in vitro and twice as potent in vivo. It is the most potent of all of the simple methyl-substituted cyclohexyl PCP isomers and is among the most potent PCP-like compounds which have been synthesized. It was nine times more potent in vitro and four times more potent in vivo than (+)-2. The racemic cis-1-(1-phenyl-2-methylcyclohexyl)piperidine (3), and its enantiomers ((+)-3 and (-)-3), were essentially inactive in vitro and in vivo. The cis-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidine (18) was more potent than trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidine (17), but considerably less potent than (-)-2. The enantioselectivity observed at the PCP binding site for (-)-2 could indicate that this site can discriminate between enantiotopic edges of the achiral PCP (choosing the pro-1-S edge), as does the mu-opioid receptor in the prodine series of opioids. Benzimidoyl or benzoyl group replacement of the phenyl ring in the 1-(1-phenyl-2-methylcyclohexyl)piperidine series gave compounds which showed little in vitro and in vivo activity.

Derivatives with fluoromethyl and hydroxymethyl groups on the cyclohexyl ring of 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptor, were tested in a radioligand binding assay to evaluate their ability to inhibit [3H]TCP binding by rat brain homogenates. The potencies of these compounds as antagonists of NMDA and L-glutamate responses were also compared using a rat cortical slice preparation. One of the analogs, cis-2-hydroxymethyl-r-1-(N-piperidyl)-1-(2-thienyl) cyclohexane (5) was found to show a high affinity (IC50 = 16 nM) for the phencyclidine (PCP) binding sites, very close to that of TCP, and to be 38-fold more potent in binding than its trans isomer. Fluoromethyl and hydroxymethyl substitutions at C4 position of the cyclohexyl ring of TCP clearly reduced the affinity by at least one order of magnitude relative to TCP.