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Jacques Vignon - One of the best experts on this subject based on the ideXlab platform.

  • Development of NMDAR Antagonists with Reduced Neurotoxic Side Effects: a Study on GK11
    2016
    Co-Authors: Lauriane Ulmann, Jacques Vignon, Alain Privat, Marisa Teigell, Regino Perez-polo, Olivera Nesic, Helene Hirbec
    Abstract:

    The NMDAR glutamate receptor subtype mediates various vital physiological neuronal functions. However, its excessive activation contributes to neuronal damage in a large variety of acute and chronic neurological disorders. NMDAR antagonists thus represent promising therapeutic tools that can counteract NMDARs ’ overactivation. Channel blockers are of special interest since they are use-dependent, thus being more potent at continuously activated NMDARs, as may be the case in pathological conditions. Nevertheless, it has been established that NMDAR antagonists, such as MK801, also have unacceptable neurotoxic effects. Presently only Memantine is considered a safe NMDAR antagonist and is used clinically. It has recently been speculated that antagonists that preferentially target extrasynaptic NMDARs would be less toxic. We previously demonstrated that the Phencyclidine Derivative GK11 preferentially inhibits extrasynaptic NMDARs. We thus anticipated that this compound would be safer than other known NMDAR antagonists. In this study we used whole-genome profiling of the rat cingulate cortex, a brain area that is particularly sensitive to NMDAR antagonists, to compare the potential adverse effects of GK11 and MK801. Our results showed that in contrast to GK11, the transcriptional profile of MK801 is characterized by a significant upregulation of inflammatory and stress-response genes, consistent with its high neurotoxicity. In addition, behavioural and immunohistochemical analyses confirmed marked inflammatory reactions (including astrogliosis an

  • Development of nmdar antagonists with reduced neurotoxic side effects: A study on GK11
    PloS one, 2013
    Co-Authors: Delphine Vandame, Jacques Vignon, Alain Privat, Lauriane Ulmann, Marisa Teigell, Regino Perez-polo, Olivera Nesic, Monica Prieto-cappellini, Helene Hirbec
    Abstract:

    The NMDAR glutamate receptor subtype mediates various vital physiological neuronal functions. However, its excessive activation contributes to neuronal damage in a large variety of acute and chronic neurological disorders. NMDAR antagonists thus represent promising therapeutic tools that can counteract NMDARs’ overactivation. Channel blockers are of special interest since they are use-dependent, thus being more potent at continuously activated NMDARs, as may be the case in pathological conditions. Nevertheless, it has been established that NMDAR antagonists, such as MK801, also have unacceptable neurotoxic effects. Presently only Memantine is considered a safe NMDAR antagonist and is used clinically. It has recently been speculated that antagonists that preferentially target extrasynaptic NMDARs would be less toxic. We previously demonstrated that the Phencyclidine Derivative GK11 preferentially inhibits extrasynaptic NMDARs. We thus anticipated that this compound would be safer than other known NMDAR antagonists. In this study we used whole-genome profiling of the rat cingulate cortex, a brain area that is particularly sensitive to NMDAR antagonists, to compare the potential adverse effects of GK11 and MK801. Our results showed that in contrast to GK11, the transcriptional profile of MK801 is characterized by a significant upregulation of inflammatory and stress-response genes, consistent with its high neurotoxicity. In addition, behavioural and immunohistochemical analyses confirmed marked inflammatory reactions (including astrogliosis and microglial activation) in MK801-treated, but not GK11-treated rats. Interestingly, we also showed that GK11 elicited less inflammation and neuronal damage, even when compared to Memantine, which like GK11, preferentially inhibits extrasynaptic NMDAR. As a whole, our study suggests that GK11 may be a more attractive therapeutic alternative in the treatment of CNS disorders characterized by the overactivation of glutamate receptors.

  • gacyclidine a new neuroprotective agent acting at the n methyl d aspartate receptor
    Cns Drug Reviews, 2006
    Co-Authors: Helene Hirbec, Manuel Gaviria, Jacques Vignon
    Abstract:

    Gacyclidine is a new Phencyclidine Derivative with neuroprotective properties. Tritiated gacyclidine and its enantiomers bind to NMDA receptors with binding parameters similar to those of other non-competitive NMDA receptor antagonists. The (-)enantiomer, (-)GK11, exhibits an affinity (2.5 nM) similar to that of dizocilpine (MK-801), while the (+)enantiomer, (+)GK11, has a 10 times lower affinity. When its interaction with NMDA receptors is prevented, gacyclidine binds also to “non-NMDA” binding sites which are mainly located in the molecular layer of the cerebellum on the dendritic tree of Purkinje cells. These binding sites do not appear to be related to any known neuro transmitters. In primary cortical cultures, gacyclidine and its enantiomers, at 0.1 to 5.0 μ, prevent glutamate-induced neuronal death. In rats, in vivo neurotoxicity of gacyclidine is far low than that of MK-801. No necrotic neurons were detected in animals sacrificed at 18 or 96 h after treatment with gacyclidine (1, 5, 10 or 20 mg/kg i.v.). At the highest (20 mg/kg) but not the lower doses (1–100 mg/kg) electron microscopy revealed the presence of few cytoplasmic or intramitochondrial vacuoles. In soman-treated monkeys gacyclidine enhanced neuroprotective activity of “three drugs cocktail” (atropine + di-azepam + pralidoxime). Moreover, in rats, gacyclidine exerts a dose- and time-dependent neuroprotection in three models of spinal cord lesion. Beneficial effects of gacyclidine include reduction of lesion size and improvement of functional parameters after injury. In traumatic brain injury models gacyclidine improves also behavioral parameters and neuronal survival. Optimal protection is obtained when gacyclidine is administered at 0 to 30 min after injury. It is, therefore, concluded that gacyclidine exhibits neuroprotective effects similar to those of other NMDA receptor antagonists, with the advantage of being substantially less neurotoxic maybe due to its interaction with “non-NMDA” binding sites.

  • Inhibition of locus coeruleus neurons by the Phencyclidine analog, N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine: evidence for potent indirect adrenoceptor agonist properties
    European Journal of Pharmacology, 1992
    Co-Authors: Karima Chergui, Jacques Vignon, Jeanmarc Kamenka, Alain Privat, Hidéo Akaoka, Jean-louis Brunet, Paul Charléty, Claude Saunier, Michel Buda, Guy Chouvet
    Abstract:

    The effects of the Phencyclidine Derivative, N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP), on the electrical activity of noradrenaline (NA) neurons of the locus coeruleus (LC) were studied in halothane-anesthetized rats. Systemic administration of BTCP potently inhibited LC neurons (ID50 of 1.1 +/- 0.1 mg/kg i.v.). This effect was mimicked by local microejection of BTCP into the LC. Both the systemic and local effects of BTCP were blocked by alpha 2-adrenoceptor antagonists and prevented by prior depletion of catecholamines with reserpine. These and other data suggest that BTCP behaves as a potent indirect NA agonist (i.e. via NA re-uptake and/or release systems).

  • Desipramine and the Phencyclidine Derivative BTCP differently inhibit [3H]TCP binding to high- and low-affinity sites.
    European journal of pharmacology, 1991
    Co-Authors: Tangui Maurice, Jacques Vignon
    Abstract:

    Abstract The effects of N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP) and desipramine on [ 3 H]N-[1-(2-thienyl)cyclohexyl]piperidine ([ 3 H]TCP) binding were investigated in vivo and in vitro. In the cerebrrum, both drugs were competitive inhibitors of high-affinity [ 3 H]TCP binding. Conversely, in the cerebellum, they were non-competitive inhibitors of low-affinity [ 3 H]TCP binding. These results imply that the different [ 3 H]TCP binding sites have distinct pharmacological properties, and show that, although chemically related to TCP, BTCP has an effect similar to that of desipramine.

Jeanmarc Kamenka - One of the best experts on this subject based on the ideXlab platform.

  • Anticonvulsant and antilethal effects of the Phencyclidine Derivative TCP in soman poisoning
    Neurotoxicology, 1994
    Co-Authors: Pierre Carpentier, Jeanmarc Kamenka, Gérard Rondouin, A. Foquin-tarricone, N. Bodjarian, Mireille Lerner-natoli, G. Blanchet, M. Denoyer, Guy Lallement
    Abstract:

    The protection afforded by TCP (thienylcylohexylpiperidine), a non-competitive blocker of N-methyl-D-aspartate (NMDA) receptors, against the seizures and lethality produced by 2 × LD50 of soman (62 μg/kg, sc), an irreversible inhibitor of cholinesterase, was studied in guinea-pigs. In the presence of additional anticholinergic medication (pyridostigmine: 0.2 mg/kg, sc, 30 min prior to soman; atropine sulphate: 5 mg/kg, im, 1 min post-soman), TCP pretreatment (2.5 mg/kg, im, 30 or 15 min prior to soman) did not generally prevent the appearance of soman-induced status epilepticus but did arrest it after 30-40 min in 80% (TCP-30 min) or 100% (TCP-15 min) of the convulsing subjects. Moreover, in all subjects treated curatively, TCP was able to interrupt ongoing status epilepticus in approximately 20, 10 or 8 min when it was administered 5, 30 or 60 min respectively after the onset of epileptiform tracings on EEG. All of these curatively administered animals survived and recovered remarkably well. On every criteria examined (latency-to-seizure arrest, 24 hr-survival rate, clinical recovery), injection of 2.5 mg/kg TCP after 90 min of seizures appeared slightly less efficient compared to earlier curative administration. Therefore, our study (a) establishes that the previously reported capacity of MK-801 (dibenzocyclohepneimine) to counteract soman toxicity is not unique and could be extended to other non-competitive inhibitors of NMDA receptors; (b) shows that TCP could easily prevent and, above all, interrupt soman-induced seizures; furthermore, TCP appears the first compound ever tested on soman poisoning that still displays satisfactory anticonvulsant activity after such a long duration of initial status epilepticus (90 min); therefore, TCP might be of special value for the delayed therapy for soman poisoning; (c) confirms that NMDA receptors are involved in the maintenance of seizures and play an important role in other processes implicated in the overall toxicity (including the lethal respiratory effects) of soman poisoning

  • Inhibition of locus coeruleus neurons by the Phencyclidine analog, N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine: evidence for potent indirect adrenoceptor agonist properties
    European Journal of Pharmacology, 1992
    Co-Authors: Karima Chergui, Jacques Vignon, Jeanmarc Kamenka, Alain Privat, Hidéo Akaoka, Jean-louis Brunet, Paul Charléty, Claude Saunier, Michel Buda, Guy Chouvet
    Abstract:

    The effects of the Phencyclidine Derivative, N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP), on the electrical activity of noradrenaline (NA) neurons of the locus coeruleus (LC) were studied in halothane-anesthetized rats. Systemic administration of BTCP potently inhibited LC neurons (ID50 of 1.1 +/- 0.1 mg/kg i.v.). This effect was mimicked by local microejection of BTCP into the LC. Both the systemic and local effects of BTCP were blocked by alpha 2-adrenoceptor antagonists and prevented by prior depletion of catecholamines with reserpine. These and other data suggest that BTCP behaves as a potent indirect NA agonist (i.e. via NA re-uptake and/or release systems).

  • Regional differences in the effect of N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP) on extracellular dopamine levels: an in vivo microdialysis study.
    Neuroscience letters, 1992
    Co-Authors: Tangui Maurice, Jeanmarc Kamenka, Francois Joseph Roman, Xavier Pascaud, J.l. Junien
    Abstract:

    N-[1-(2-Benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP) is a Phencyclidine Derivative highly selective for the dopamine (DA) uptake complex. Its effect on extracellular DA levels was studied by in vivo microdialysis on freely moving rats. In the striatum, BTCP induced a dose-dependent increase in DA levels, without affecting DA metabolites. In the nucleus accumbens, a lower increase in DA was observed, but with concomitant decreases in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). These experiments show that the effects of BTCP on extracellular DA levels are significantly different on extrapyramidal and mesolimbic dopaminergic terminals.

  • Binding properties of 3-[125I]iodoPhencyclidine, a new radioligand for N-methyl-D-aspartate-gated ionic channels
    Journal of neurochemistry, 1992
    Co-Authors: Robert Chicheportiche, Jeanmarc Kamenka, Janique Guiramand, Michel Ponchant, Jean Pierre Beaucourt
    Abstract:

    The binding properties of the 125I-labeled Phencyclidine Derivative N-[1-(3-[125I]iodophenyl)cyclohexyl]piperidine (3-[125I]iodo-PCP), a new ligand of the N-methyl-D-aspartate (NMDA)-gated ionic channel, were investigated. Association and dissociation kinetic curves of 3-[125I]iodo-PCP with rat brain homogenates were well described by two components. About 32% of the binding was of fast association and fast dissociation, and the remaining binding was of slow association and slow dissociation. Saturation curves of 3-[125I]iodo-PCP also were well described using two binding sites: one of a high affinity (KDH = 15.8 +/- 2.3 nM) and the other of a low affinity (KDL = 250 +/- 40 nM). 3-Iodo-PCP inhibited the binding of 3-[125I]iodo-PCP with inhibition curves that were well fitted by a two-site model. The binding constants (KiH, BmaxH; KiL, BmaxL) so obtained were close to those obtained in saturation experiments. Ligands of NMDA-gated ionic channels also inhibited the binding of 3-[125I]iodo-PCP with two constants, KiH and KiL. There was a very good correlation (r = 0.987) between the affinities of these ligands to bind to NMDA-gated ionic channels and their potencies to inhibit the binding of 3-[125I]iodo-PCP with a high affinity. Moreover, the regional distribution of the high-affinity binding of 3-[125I]-iodo-PCP paralleled that of tritiated N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP). In contrast to that of [3H] TCP, the binding of 3-[125I]iodo-PCP to well-washed rat brain membranes was fast and insensitive to glutamate and glycine.(ABSTRACT TRUNCATED AT 250 WORDS)

  • dopamine modulates 3h btcp a Phencyclidine Derivative binding to the dopamine uptake complex
    Presynaptic Receptors and Neuronal Transporters#R##N#Official Satellite Symposium to the IUPHAR 1990 Congress Held in Rouen France on 26–29 June 1990, 1991
    Co-Authors: Jacques Vignon, Tangui Maurice, Gerard Barbanel, Jeanmarc Kamenka
    Abstract:

    ABSTRACT The effect of dopamine (DA) on [3H]N-[1-(benzo(b)thiophenyl)cyclohexyl] piperidine ([3H]BTCP, a Phencyclidine Derivative) binding to the dopamine uptake complex has been investigated in vitro (rat striatal membranes) and in vivo (mouse brain). In both binding assays DA was found to behave as a non competitive inhibitor of [3H]BTCP binding. These results suggest the presence of a DA uptake modulatory site distinct from the DA recognition site on the carrier.

Tangui Maurice - One of the best experts on this subject based on the ideXlab platform.

  • Regional differences in the effect of N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP) on extracellular dopamine levels: an in vivo microdialysis study.
    Neuroscience letters, 1992
    Co-Authors: Tangui Maurice, Jeanmarc Kamenka, Francois Joseph Roman, Xavier Pascaud, J.l. Junien
    Abstract:

    N-[1-(2-Benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP) is a Phencyclidine Derivative highly selective for the dopamine (DA) uptake complex. Its effect on extracellular DA levels was studied by in vivo microdialysis on freely moving rats. In the striatum, BTCP induced a dose-dependent increase in DA levels, without affecting DA metabolites. In the nucleus accumbens, a lower increase in DA was observed, but with concomitant decreases in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). These experiments show that the effects of BTCP on extracellular DA levels are significantly different on extrapyramidal and mesolimbic dopaminergic terminals.

  • Desipramine and the Phencyclidine Derivative BTCP differently inhibit [3H]TCP binding to high- and low-affinity sites.
    European journal of pharmacology, 1991
    Co-Authors: Tangui Maurice, Jacques Vignon
    Abstract:

    Abstract The effects of N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP) and desipramine on [ 3 H]N-[1-(2-thienyl)cyclohexyl]piperidine ([ 3 H]TCP) binding were investigated in vivo and in vitro. In the cerebrrum, both drugs were competitive inhibitors of high-affinity [ 3 H]TCP binding. Conversely, in the cerebellum, they were non-competitive inhibitors of low-affinity [ 3 H]TCP binding. These results imply that the different [ 3 H]TCP binding sites have distinct pharmacological properties, and show that, although chemically related to TCP, BTCP has an effect similar to that of desipramine.

  • dopamine modulates 3h btcp a Phencyclidine Derivative binding to the dopamine uptake complex
    Presynaptic Receptors and Neuronal Transporters#R##N#Official Satellite Symposium to the IUPHAR 1990 Congress Held in Rouen France on 26–29 June 1990, 1991
    Co-Authors: Jacques Vignon, Tangui Maurice, Gerard Barbanel, Jeanmarc Kamenka
    Abstract:

    ABSTRACT The effect of dopamine (DA) on [3H]N-[1-(benzo(b)thiophenyl)cyclohexyl] piperidine ([3H]BTCP, a Phencyclidine Derivative) binding to the dopamine uptake complex has been investigated in vitro (rat striatal membranes) and in vivo (mouse brain). In both binding assays DA was found to behave as a non competitive inhibitor of [3H]BTCP binding. These results suggest the presence of a DA uptake modulatory site distinct from the DA recognition site on the carrier.

  • Modulation by dopamine of [3H]N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine ([3H]BTCP, a Phencyclidine Derivative) binding to the dopamine uptake complex.
    Neuropharmacology, 1991
    Co-Authors: Tangui Maurice, Gerard Barbanel, Jeanmarc Kamenka, Jacques Vignon
    Abstract:

    The modulation by dopamine of the binding of [3H]BTCP to the dopamine (DA) uptake complex was investigated in vivo (in control, reserpine- and L-DOPA-treated mice) and in vitro (on membrane preparations of the striatum of the rat). In both cases increasing doses of DA exerted a non-competitive inhibition of binding of [3H]BTCP, with a Ki value close to its K0.5, determined in competition experiments. Amphetamine and cocaine were also non-competitive inhibitors of the binding of [3H]BTCP, while GBR 12783 was competitive. In the presence of DA, the amount of cocaine required to inhibit the binding of [3H]BTCP was increased both in vitro and in vivo. These results suggest that inhibitors of the uptake of DA, such as BTCP or GBR 12783, modulate allosterically the uptake of DA, by binding to a site different from the DA recognition site. Cocaine, however, seems to share the same recognition site as DA.

Guy Chouvet - One of the best experts on this subject based on the ideXlab platform.

Alain Privat - One of the best experts on this subject based on the ideXlab platform.

  • Development of NMDAR Antagonists with Reduced Neurotoxic Side Effects: a Study on GK11
    2016
    Co-Authors: Lauriane Ulmann, Jacques Vignon, Alain Privat, Marisa Teigell, Regino Perez-polo, Olivera Nesic, Helene Hirbec
    Abstract:

    The NMDAR glutamate receptor subtype mediates various vital physiological neuronal functions. However, its excessive activation contributes to neuronal damage in a large variety of acute and chronic neurological disorders. NMDAR antagonists thus represent promising therapeutic tools that can counteract NMDARs ’ overactivation. Channel blockers are of special interest since they are use-dependent, thus being more potent at continuously activated NMDARs, as may be the case in pathological conditions. Nevertheless, it has been established that NMDAR antagonists, such as MK801, also have unacceptable neurotoxic effects. Presently only Memantine is considered a safe NMDAR antagonist and is used clinically. It has recently been speculated that antagonists that preferentially target extrasynaptic NMDARs would be less toxic. We previously demonstrated that the Phencyclidine Derivative GK11 preferentially inhibits extrasynaptic NMDARs. We thus anticipated that this compound would be safer than other known NMDAR antagonists. In this study we used whole-genome profiling of the rat cingulate cortex, a brain area that is particularly sensitive to NMDAR antagonists, to compare the potential adverse effects of GK11 and MK801. Our results showed that in contrast to GK11, the transcriptional profile of MK801 is characterized by a significant upregulation of inflammatory and stress-response genes, consistent with its high neurotoxicity. In addition, behavioural and immunohistochemical analyses confirmed marked inflammatory reactions (including astrogliosis an

  • Development of nmdar antagonists with reduced neurotoxic side effects: A study on GK11
    PloS one, 2013
    Co-Authors: Delphine Vandame, Jacques Vignon, Alain Privat, Lauriane Ulmann, Marisa Teigell, Regino Perez-polo, Olivera Nesic, Monica Prieto-cappellini, Helene Hirbec
    Abstract:

    The NMDAR glutamate receptor subtype mediates various vital physiological neuronal functions. However, its excessive activation contributes to neuronal damage in a large variety of acute and chronic neurological disorders. NMDAR antagonists thus represent promising therapeutic tools that can counteract NMDARs’ overactivation. Channel blockers are of special interest since they are use-dependent, thus being more potent at continuously activated NMDARs, as may be the case in pathological conditions. Nevertheless, it has been established that NMDAR antagonists, such as MK801, also have unacceptable neurotoxic effects. Presently only Memantine is considered a safe NMDAR antagonist and is used clinically. It has recently been speculated that antagonists that preferentially target extrasynaptic NMDARs would be less toxic. We previously demonstrated that the Phencyclidine Derivative GK11 preferentially inhibits extrasynaptic NMDARs. We thus anticipated that this compound would be safer than other known NMDAR antagonists. In this study we used whole-genome profiling of the rat cingulate cortex, a brain area that is particularly sensitive to NMDAR antagonists, to compare the potential adverse effects of GK11 and MK801. Our results showed that in contrast to GK11, the transcriptional profile of MK801 is characterized by a significant upregulation of inflammatory and stress-response genes, consistent with its high neurotoxicity. In addition, behavioural and immunohistochemical analyses confirmed marked inflammatory reactions (including astrogliosis and microglial activation) in MK801-treated, but not GK11-treated rats. Interestingly, we also showed that GK11 elicited less inflammation and neuronal damage, even when compared to Memantine, which like GK11, preferentially inhibits extrasynaptic NMDAR. As a whole, our study suggests that GK11 may be a more attractive therapeutic alternative in the treatment of CNS disorders characterized by the overactivation of glutamate receptors.

  • Prevention of nimodipine-induced impairment of learning by the selective sigma ligand PRE-084.
    Journal of neural transmission. General section, 1995
    Co-Authors: T. Maurice, D. W. Parish, Alain Privat
    Abstract:

    The high selectivity of the Phencyclidine Derivative PRE-084 for sigma (σ) sites is demonstrated. We previously reported that this compound is able to markedly attenuate the impairment of learning induced in mice by the non-competitive NMDA antagonist MK-801, and the cholinergic nicotinic antagonist mecamylamine. In this study, we examined the effect of PRE-084 on the impairment of learning induced by acute administration of the calcium channel antagonist nimodipine. Nimodipine (0.3mg/kg i.p.) impaired the spontaneous alternation behaviour in a Y-maze, decreased the step-down latency (SDL) in a passive avoidance task, and altered place learning and retention in a water-maze paradigm, with no marked effect on the motility observed using an open-field test. Preadministration of PRE-084 resulted in an attenuation of the impairment of alternation, in the 0.3–1 mg/kg s.c. range, in a marked increase in SDL, at 1–3 mg/kg, and improved place learning and retention in the water-maze, at 1 mg/kg. The effects on alternation behaviour and passive avoidance were completely prevented by co-administration of the purported σ antagonist BMY-14802 (10 mg/kg i.p.), implicating the σ sites. These results confirm the beneficial effect of the σ ligand PRE-084 on pharmacological models of learning impairments, and indicate that σ sites may modulate Ca2+ fluxes through VDCC, which may in turn bear some as yet unknown relationship to the previously described interaction with neurotransmitter systems.

  • Inhibition of locus coeruleus neurons by the Phencyclidine analog, N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine: evidence for potent indirect adrenoceptor agonist properties
    European Journal of Pharmacology, 1992
    Co-Authors: Karima Chergui, Jacques Vignon, Jeanmarc Kamenka, Alain Privat, Hidéo Akaoka, Jean-louis Brunet, Paul Charléty, Claude Saunier, Michel Buda, Guy Chouvet
    Abstract:

    The effects of the Phencyclidine Derivative, N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP), on the electrical activity of noradrenaline (NA) neurons of the locus coeruleus (LC) were studied in halothane-anesthetized rats. Systemic administration of BTCP potently inhibited LC neurons (ID50 of 1.1 +/- 0.1 mg/kg i.v.). This effect was mimicked by local microejection of BTCP into the LC. Both the systemic and local effects of BTCP were blocked by alpha 2-adrenoceptor antagonists and prevented by prior depletion of catecholamines with reserpine. These and other data suggest that BTCP behaves as a potent indirect NA agonist (i.e. via NA re-uptake and/or release systems).