Tenocyclidine

Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds

Pharmaceuticals -> Listed in ZINC15

Schedule I shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation, which contains any quantity of the following hallucinogenic substances, or which contains any of its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation (for purposes of this paragraph only, the term "isomer" includes the optical, position and geometric isomers). 1-(1-(2-Thienyl)cyclohexyl)piperidine (DEA Code Number: 7470) is included on this list.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The capacity of thienylcyclohexylpiperidine (TCP), a non-competitive blocker of the N-methyl-D-aspartate (NMDA) receptor, to counteract the convulsant, lethal, and neuropathological effects of 2 x LD50 of soman (an irreversible inhibitor of cholinesterase) was investigated in guinea-pigs treated by pyridostigmine and atropine sulfate. The effects of a weak dose of TCP (1 mg/kg) used in the present study globally reproduced those previously obtained with a higher dose (2.5 mg/kg ... ): TCP was again most protective when given curatively within the first hour of soman-induced seizures. In this condition, (a) paroxysmal activity ceased in 10-20 min, (b) all the animals survived, (c) the majority of them recovered remarkably well and did not show any brain damage 24 hr after the intoxication, and (d) the minimal duration of seizure activity normally required for producing soman-induced brain damage in other pharmacological environments was increased from 10 to 40 min to 80 min. Strikingly, when TCP was given 120 min after seizure onset, it failed to show any anticonvulsant activity but still provided neuroprotection in the hippocampus. The present study also gives additional evidence ... that in soman poisoning, (a) the development of brain damage depends on the occurrence of ECoG seizures, (b) the topographical distribution of lesions depends on seizure duration, and (c) an increase of the relative power in the lowest (delta) frequency band might be a reliable marker of neuronal degradation. All these findings confirm that (a) glutamatergic NMDA receptors are involved in the mechanisms of soman-induced seizures and brain damage, (b) non-competitive antagonists of NMDA receptors might be promising candidates for post-treatment of soman poisoning, and (c) ECoG parameters from ECoG tracings and power spectrum might serve as useful external predictors for soman-induced neuropathological changes.

... Benzodiazepines, the most potent of the clinically available anticonvulsants are potentially useful as antidote against nerve agent poisoning. However, significant disadvantages are associated with the im administration of benzodiazepines particularly diazepam ... . The present report was undertaken to compare the effectiveness of thienyl phencyclidine (TCP), a non-competitive antagonist at N-methyl-D-aspartate (NMDA) glutamate receptors, to diazepam both administered im for protection against soman toxicity (convulsions, seizures, incidence on death, brain damage). In a first set of experiments, male Wistar rats were pretreated with diazepam (1 mg/kg) given im. Fifteen minutes later 1 x LD50 of soman was injected sc and the incidence of seizures and death were recorded for 24 hr. The therapeutic efficacy of a post-poisoning treatment of diazepam was also studied. In this case diazepam was administered 45 min after the onset of seizures. In a second set of experiments, guinea-pigs were pretreated with pyridostigmine (0.2 mg/kg, sc) in combination with atropine (5 mg/kg, im) 30 min before soman (62 micrograms/kg, sc) and the protective effect of TCP (2.5 mg/kg, im) evaluated when the drug was administered either before soman (15 or 30 min) or after the onset of EEG seizures (5, 30 or 60 min). Pretreatment with diazepam alone did reduce soman-induced seizures but did not reduce mortality of rats. Neuropathology was not observed in non-seizuring rats. When given 45 min after the onset of seizures, diazepam failed to protect against status epilepticus and neuropathology. Thus, diazepam was more effective when given before, rather than after, seizure initiation. Systemic injection of TCP blocked the seizures induced by 2 x LD50 of soman in guinea-pigs pretreated by pyridostigmine and atropine. The anticonvulsant potency of TCP was particularly obvious when the compound was administered curatively.

The intrahippocampal injection of two agonists of excitatory aminoacid (EAA) receptors elicited neuronal damages localized in CA1 and dentate gyrus for N-methyl-D-aspartate (NMDA) (20 nmol) and extended to the various hippocampal areas, except dentate gyrus for kainic acid (KA) (2.5 nmol). The pretreatment of the animals with N-[1-(2-thienyl)cyclohexyl]piperidine (TCP) (20 mg/kg), a noncompetitive NMDA-receptor antagonist, prevented the neuronal injury induced by NMDA and KA in CA1. The distribution of neuronal damages and of TCP-protected areas closely correlated to that of EEA-receptors and of TCP binding sites in the hippocampus.

The ability of relatively low doses of atropine, 2,3-Dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX) and TCP administered in combination to prevent or stop seizures induced by soman, was studied in rats. While these drugs injected together early after soman prevented the onset of seizures, their delayed concomitant administration after 5 or 30 min of epileptic activity only mildly attenuated the intensity of seizures. Conversely, a total arrest of epileptic activity was observed in 80 to 100% of animals when NBQX and TCP were given together after 5 to 50 min of seizures to atropine pretreated rats. The large time-window for antiepileptic effectiveness of this 'three drug treatment', provided that atropine is administered early after soman, is discussed in relation to reciprocal potentiations of the antiepileptic effects of atropine, NBQX and TCP in combination.

For more Interactions (Complete) data for TENOCYCLIDINE (11 total), please visit the HSDB record page.

/ALTERNATIVE and IN VITRO TESTS/ ... In vitro interactions of Tenocyclidine (TCP)and its adamantane derivative--TAMORF with human erythrocyte acetylcholinesterase (AChE) /were investigated/. Moreover, their genotoxicity and radioprotective activity on human white blood cells were studied using the alkaline comet assay, viability testing and the analysis of the structural chromosome aberrations. The tested compounds were ... weak inhibitors of AChE, for TCP IC(50)=1 x 10-5 M and for TAMORF IC(50)>1 x 10-3 M, without reactivating and protective effects on AChE inhibited by soman. Results suggest that TCP modified by the replacement of the cyclohexyl ring with an adamantane ring and piperidine with morpholine group (TAMORF) have lower toxicity. Both compounds possess low cytotoxicity and radioprotective activity, but TAMORF also shows cell growth inhibitory effects. ... Since TAMORF was found to significantly inhibit cell growth and proliferation in vitro, it is reasonable to consider it as a source molecule promising for further modifications and development of more potent substances with antitumor properties rather than radioprotector or antidote in organophosphorus poisoning.

/LABORATORY ANIMALS: Acute Exposure/ A series of phencyclidine (PCP) related analogs ... were compared pharmacologically in mice for their ability to produce ataxia using the rotarod method and toxicologically for their acute 4-hr lethality. ... Responses for all analogs, metabolites and precursors produced curves parallel to that of PCP. Ataxia potencies of all PCP-related compounds ranged from 0.05 to 2.15 times PCP and durations of action ranged from 18 to 65 min. N-ethyl-1-phenylcyclohexylamine, 1-[1-(2-thienyl)-cyclohexyl]-piperidine and 1-[1-(2-thienyl)-cyclohexyl]-pyrrolidine were most potent and least potent were 1-(1-phenyl-cyclohexyl)-4-methylpiperidine, the phenyl and thienyl morpholines and 4-phenyl-4-piperidinocyclohexanol. Among the PCP analogs, modifying the piperidine or aromatic ring effected changes only in potency. Seizures and respiratory depression characterized the lethal effects of PCP, its analogs, metabolites and precursors. However, the precursors failed to elicit the stereotyped movements and hyperactivity that preceded seizures produced by the other compounds. Overall potencies for lethality relative to PCP covered a narrow range (0.16-1.83) with the carbonitrile precursors being most potent. Therapeutic indices indicated relatively large margins of safety for 1-[1-(2-thienyl)-cyclohexyl]-piperidine, 1-[1-(2-thienyl)-cyclohexyl]-piperidine, N-ethyl-1-phenylcyclohexylamine and ketamine and the smallest were for 1-(1-phenylcyclohexyl)-4-methylpiperidine, the metabolite 4-phenyl-4-piperidinocyclohexanol and the three precursors.

/LABORATORY ANIMALS: Neurotoxicity/ TCP (N-[1-(2-thienyl)cyclohexyl]piperidine), a PCP (phencyclidine) derivative, has been shown to possess antiepileptic and neuroprotective efficacy against chemically induced seizures. However, it is known that other antagonists of the NMDA receptor impair spatial learning. This study was thus undertaken to explore the eventual effects of TCP on memory. The same study was done with MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine ), one of the most studied NMDA receptor antagonists, which can be considered as a reference molecule. Three doses of each drug were chosen: 0.05, 0.1, and 0.2 mg/kg for MK-801 and 0.5, 1, and 2 mg/kg for TCP, the second dosage corresponding to the minimal required for antiseizure activity. The drugs were injected IP 30 min each day before a classical procedure of acquisition in a Morris water maze test. At the highest dose of each drug, the animals did not learn the position of the platform. At 0.1 mg/kg MK-801, the rats used a praxis strategy to find the platform but they did not known where the platform was. Contrary to MK-801, TCP at 1 mg/kg did not induce any memory impairment. At the lowest doses used, no memory impairment was found. It thus appears that, at the minimal therapeutic dose effective against chemically induced seizures (0.1 mg/kg for MK-801 and 1 mg/kg for TCP), TCP, contrary to MK-801, does not induce any memory impairment. Furthermore, at all the doses used, TCP presents the particularity that its locomotor side effects are not long lasting, being no longer observed from 30 min after the injection.

/LABORATORY ANIMALS: Neurotoxicity/ Phencyclidine (1-(1-phenylcyclohexyl)piperidine, PCP) self-administration has been demonstrated in rhesus monkeys, baboons, dogs and rats. Generally, an orderly inverted U-shaped dose-response curve for rates of self-injection has been observed. Total drug intake appears to increase slightly with increases in unit dose; however, this increase is much less than might be expected with other CNS depressants such as barbiturates or morphine. Additionally, several arylcyclohexylamine analogues of PCP and some members of the benzomorphan and dioxolane classes referred to collectively as "phencyclinoids" are self-administered by primates and dogs. New data are presented in this review profiling the self-administration of some of these drugs in rats, as well as a characterization of the self-administration of higher unit doses of PCP than previously reported. Also, preliminary results of the assessment of the reinforcing efficacy of some PCP analogues measured by the progressive ratio procedure are presented. /Phencyclinoids/

/LABORATORY ANIMALS: Neurotoxicity/ /Locomotion, stereotypy, and ataxia /in rats/ were rated via behavioral observations for all compounds, using behavioral rating scales devised specifically for PCP ... Behaviors were rated by observing each animal for 1 or 2 minutes at the midpoint of each 30-minute dosing interval during collection of the EEG.PCP increased behavioral rating scores for stereotypy and ataxia as a function of increasing dose, from 0.2 to 3.2 mg/kg cumulative IV. For PCP-induced locomotion, behavioral rating scores increased up to 1.6 mg/kg, and declined at 3.2 mg/kg. Similar scores were generated for the other compounds over doses ranging from 0.1 to 12.8 mg/kg. When scores for one behavior increased, concomitant increases in the scores for each of the behaviors resulted, making only quantitative differences between these phencyclinoids observable. Consequently, similar relative potencies were obtained from consideration of any one of these three behaviors. The rank order of potency for locomotion, stereotypy, and ataxia was TCP > PCP = PCPY = TCPY > PCE = NsBPCA > NMPCA > ketamine = PCA = SKF-10,047. PCE was unusual in that its potency for ataxia was nearly equal to PCP's, yet it was only about one-third as potent in inducing locomotion and about two-thirds as potent for producing stereotypy. TCP was more potent, TCPY and PCPY were about equipotent, and PCA was less potent than PCP.

For more Non-Human Toxicity Excerpts (Complete) data for TENOCYCLIDINE (6 total), please visit the HSDB record page.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR as necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Incapacitating Agents/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations it necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . Demonstrate a friendly attitude and use firm restraint when necessary. All dangerous objects must be removed from the area and anything likely to be swallowed should be kept away from patients, because bizarre delusions may occur. For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Use rapid cooling techniques to manage hyperthermia ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Incapacitating Agents/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Treat seizures or sedate ... patients with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Incapacitating Agents/

Schedule I shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation, which contains any quantity of the following hallucinogenic substances, or which contains any of its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation (for purposes of this paragraph only, the term "isomer" includes the optical, position and geometric isomers). 1-(1-(2-Thienyl)cyclohexyl)piperidine (DEA Code Number: 7470) is included on this list.

The primary interactions are as a non-competitive antagonist at the 3A-subunit of the NMDAR in Homo sapiens. TCP is known to bind, with relatively high affinity, to the D1 subunit of the human DAT, in addition to displaying a positive antagonistic effect at the α7-subunit of the Nicotinic Acetylcholine Receptor (nAChR). It also binds to the mu-opioid receptor, which seems to be a central part of the mechanism of action of drugs in this class. (For example, Dizocilpine [MK-801] shows little appreciable analgesic effect despite having a high specificity for the NMDA-3A and NMDA-3B subunits - this may well be mediated by the lack of related efficacy at the mu-opioid receptor, though the NMDAR certainly does play a role in transmission of pain signals).

Phencyclidine induces a model psychosis which can persist for prolonged periods and presents a strong drug model of schizophrenia. When given continuously for several days to rats, phencyclidine and other N-methyl-D-aspartate (NMDA) antagonists induce neural degeneration in a variety of limbic structures, including retrosplenial cortex, hippocampus, septohippocampal projections, and piriform cortex. In an attempt to further clarify the mechanisms underlying these degeneration patterns, autoradiographic studies using a variety of receptor ligands were conducted in animals 21 days after an identical dosage of the continuous phencyclidine administration employed in the previous degeneration studies. The results indicated enduring alterations in a number of receptors: these included decreased piperidyl-3,4-3H(N)-TCP (TCP), flunitrazepam, and mazindol binding in many of the limbic regions in which degeneration has been reported previously. Quinuclidinyl benzilate and (AMPA) binding were decreased in anterior cingulate and piriform cortex, and in accumbens and striatum. Piperidyl-3,4-3H(N)-TCP binding was decreased in most hippocampal regions. Many of these long-term alterations would not have been predicted by prior studies of the neurotoxic effects of continuous phencyclidine, and these results do not suggest a unitary source for the neurotoxicity. Whereas retrosplenial cortex, the structure which degenerates earliest, showed minimal alterations, some of the most consistent, long term alterations were in structures which evidence no immediate signs of neural degeneration, such as anterior cingulate cortex and caudate nucleus. In these structures, some of the receptor changes appeared to develop gradually (they were not present immediately after cessation of drug administration), and thus were perhaps due to changed input from regions evidencing neurotoxicity. Some of these findings, particularly in anterior cingulate, may have implications for models of schizophrenia.

1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) and its derivative gacyclidine (+/- GK11) are high-affinity non-competitive antagonists of N-methyl-D-aspartate (NMDA) receptors (NMDARs) and as such exhibit significant neuroprotective properties. These compounds also bind with a low affinity to binding sites whose pharmacological profiles are different from that of NMDARs. /The purpose of this study was to/ whether TCP and gacyclidine low-affinity sites are similar. The effects of several drugs selective for either NMDARs or the [(3)H]TCP low-affinity site (or PCP(3) site) on (+), (-)[(3)H]GK11 and [(3)H]TCP specific binding were investigated. Competition experiments on cerebellum homogenates revealed substantial differences between the pharmacological profiles of the PCP(3) site and that of gacyclidine's enantiomers low-affinity sites. Under experimental conditions preventing the interaction of the radioligands with NMDARs, the autoradiographic study showed, however, that the distributions of both [(3)H]TCP and (-)[(3)H]GK11 specific binding were similar. The specific labelling was low and uniform in telencephalic structures, whereas in the cerebellum it was higher in the molecular than in the granular layer. Finally, the analysis of competition experiments performed on tissue slices demonstrated that PCP(3) selective ligands were unable to prevent [(3)H]TCP or (-)[(3)H]GK11 binding to "non-NMDA" binding sites...

The voltage-dependent block of NMDA channels by Mg2+ is an important functional element of NMDA receptors, since relief of block by depolarization plays a key role in some forms of ischemic neurodegeneration and synaptic plasticity. To identify the relevant structural domains responsible for block by Mg2+ and TCP, ... site-directed mutagenesis /was used/ to change individual amino acids of the rat NR1A subunit in a transmembrane region (599-DALTLSSAMWFSWGVLLNSGIGE-621, mutated residues underlined) previously shown to donate residues that influence ionic selectivity. Ten mutant NR1A subunits were co-expressed in Xenopus oocytes with either the epsilon 1 or NR2A subunits, and receptor properties were analyzed under two-electrode voltage clamp. The mutation N616R virtually abolished voltage-dependent Mg2+ block, reduced Zn2+ block 5-fold and greatly reduced Ba2+ permeability in confirmation of previous reports. This mutation also reduced the potency of TCP as a use-dependent blocker by 200-fold. The remaining low-affinity TCP block did not appear to be use-dependent, suggesting two blocking sites for TCP. None of the other mutations differed significantly from NR1A itself except S617N, which displayed a 6-fold reduction in Mg2+ block. A well-barrier model of permeation through the NMDA receptor channel is presented that quantitatively reproduces voltage-dependent Mg2+ block. This model demonstrates that only minimum changes /of/ energy profiles experienced by permeating ions, equivalent to the energy of a single hydrogen or ionic bond, are required to abolish Mg2+ block. These findings indicate that only small structural changes are needed to convert a Mg(2+)-insensitive ion channel to a channel with pronounced voltage-dependent Mg2+ block.

Results of correlation analyses comparing rank-order affinities with rank-order potencies of (+)SKF-10,047, phencyclidine (PCP), and several PCP analogs support the involvement of [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine binding sites (TCP sites) in mediating both the discriminative stimulus properties of PCP and production of 180 degrees perseveration in a 4-arm radial maze. For the same group of drugs, no significant relationship was found to exist between affinities at haloperidol-sensitive (+)[3H]SKF-10,047 binding sites (H-S-SKF sites) and potencies. Also, H-S-SKF sites were found to lack pharmacological selectivity and to be localized in the microsomal fraction of cells. It is concluded that TCP sites may represent receptors which mediate effects not only of PCP, but also of (+)SKF-10,047. In addition, the possibility that H-S-SKF sites may represent a type of membrane-bound enzyme is discussed.

The polyamine competitive antagonist arcaine (1,4-diguanidino-butane) produced complete inhibition of basal [3H]N-(1-[thienyl] cyclohexyl)piperidine ([3H]TCP) binding, with an IC50 value of 4.52 +/- 0.93 uM. Arcaine (5 and 10 uM) produced a decrease in the affinity without a significant change in the receptor density of [3H]TCP binding under equilibrium conditions. In addition, arcaine did not alter either N-methyl-D-aspartate-specific [3H] glutamate or strychnine-insensitive [3H]glycine binding. Furthermore, increasing concentrations of arcaine produced parallel rightward shifts in the concentration-response curves for both spermidine- and magnesium-induced [3H]TCP binding, suggesting that arcaine is a competitive inhibitor of both agonists. Similar rightward shifts were observed for barium- and strontium-induced [3H]TCP binding. In contrast, arcaine decreased the efficacy of glutamate- and glycine-induced [3H]TCP binding without changing their EC50 values, indicating a noncompetitive type of inhibition. These results imply that spermidine and certain divalent cations including magnesium share the same mechanism for enhancing [3H]TCP binding, whereas glutamate and glycine have different sites of action. This is further supported by the additive effect of spermidine when tested in the presence of maximal concentrations of glutamate and glycine. On the other hand, spermidine and magnesium were not additive and, in fact, magnesium was able to block the effects of spermidine under certain conditions. The possibility that magnesium is a partial agonist at the polyamine site is discussed.

Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids.

Legal Status: Schedule 1 list of illegal drugs/Class A (Germany)

Pretreatment with tenocyclidine or its adamantyl-morphine derivative ... proved very effect against Soman when given to mice 15 before Soman ...

... may be useful for alleviating toxicity experienced by millions of /cocaine/ addicts