PCP Receptor Research Articles

Synthesis of conformationally restricted 1,3-dioxanes to analyze the bioactive conformation of 1,3-dioxane-based σ1 and PCP receptor antagonists

The receptor binding profile of 2-phenyl-4-(aminoethyl)-1,3-dioxanes is dependent on the additional substituent in 2-position, the substituents at the amino moiety and the stereochemistry. Herein, conformationally restricted 1,3-dioxanes bearing an axially oriented phenyl moiety in 2-position were prepared and pharmacologically evaluated. Two subsequent intramolecular transacetalization reactions represent the key steps in the synthesis of the tricyclic system. The resulting alcohol 17 was transformed into amines 20–23 with axially (a-series) or equatorially oriented aminoethyl moiety (b-series). The primary amines 20a and 20b did not interact with the PCP binding site of the NMDA receptor, which is explained by the additional methylene moiety between the acetalic center and the phenyl moiety, the missing substituent at the acetalic position and/or a non-optimal three-dimensional arrangement of the pharmacophoric elements. The benzylamine 21b with an equatorially oriented aminoethyl moiety shows high σ1 affinity (Ki=5.9nM). Compared with the conformationally flexible 1,3-dioxane 5, the σ1 affinity of 21b is 3-fold and the σ1/σ2 selectivity is 5-fold increased.

Prediction of adherent placenta with placenta previa using a novel scoring system

Employing rats trained to discriminate 5 mg/kg of the benzomorphan opioid (+)N-allylnormetazocine [(+)NANM] from vehicle, tests of stimulus generalization and antagonism were conducted to determine the influence of several potential σ-receptor ligands. It has been previously suggested that the (+)NANM stimulus may involve concurrent action at σ- and phencyclidine (PCP) receptors. Although the low-affinity σ-antagonist rimcazole was without stimulus-attenuating effect, three novel σ-ligands-(-)PPAP, CNS 3018, and CNS 3093 (ID50 doses = 3.2, 6.7, and 4.5 mg/kg, respectively)-antagonized the (+)NANM stimulus in a dose-related fashion. The nonselective serotonergic agent 1-(3-trifluoromethyl)phenylpiperazine (TFMPP) produced partial generalization in (+)NANM-trained animals whereas buspirone, a 5-hydroxytryptamine1A (5-HT1A) agonist, attenuated (to 27% drug-appropriate responding) the (+)NANM stimulus. Because the prototypic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) failed to attenuate the (+)NANM stimulus at pharmacologically relevant doses, it seems unlikely that the (+)NANM stimulus involves a 5-HT1A mechanism. TFMPP and buspirone display modest affinity for σ-receptors and this may account for the present findings with these agents. The present results neither establish a role for σ involvement in the stimulus properties of (+)NANM nor eliminate a role for PCP receptors. They do, however, demonstrate that σ-ligands with little to no affinity for PCP receptors are capable of antagonizing the (+)NANM stimulus.

Effects of the psychotomimetic benzomorphan N-allylnormetazocine (SKF 10,047) on prepulse inhibition of startle in mice

N-allylnormetazocine (NANM; SKF 10,047) is a benzomorphan opioid that produces psychotomimetic effects. (+)-NANM is the prototypical agonist for the sigma-1 (σ1) receptor, and there is a widespread belief that the hallucinogenic effects of NANM and other benzomorphan derivatives are mediated by interactions with σ1 sites. However, NANM is also an agonist at the κ opioid receptor (KOR) and binds to the PCP site located within the channel pore of the NMDA receptor, interactions that could potentially contribute to the effects of NANM. NMDA receptor antagonists such as phencyclidine (PCP) and ketamine are known to disrupt prepulse inhibition (PPI) of acoustic startle, a measure of sensorimotor gating, in rodents. We recently found that racemic NANM disrupts PPI in rats, but it is not clear whether the effect is mediated by blockade of the NMDA receptor, or alternatively whether interactions with KOR and σ1 receptors are involved. The present studies examined whether NANM and its stereoisomers alter PPI in C57BL/6J mice, and tested whether the effects on PPI are mediated by KOR or σ1 receptors. Racemic NANM produced a dose-dependent disruption of PPI (3–30mg/kg SC). (+)-NANM also disrupted PPI, whereas (−)-NANM was ineffective. Pretreatment with the selective KOR antagonist nor-binaltorphimine (10mg/kg SC) or the selective σ1 antagonist NE-100 (1mg/kg IP) failed to attenuate the reduction in PPI produced by racemic NANM. We also found that the selective KOR agonist (−)-U-50,488H (10–40mg/kg SC) had no effect on PPI. These findings confirm that NANM reduces sensorimotor gating in rodents, and indicate that the effect is mediated by interactions with the PCP receptor and not by activation of KOR or σ1 receptors. This observation is consistent with evidence indicating that the σ1 receptor is not linked to hallucinogenic or psychotomimetic effects.

Synthesis and Analgesic Properties of New Modified Analogs of Phencyclidine with Specific Binding on PCP Receptor or Dopamine Inhibition Reuptake Activities

Phencyclidine (PCP, I) and many of its analogs have showed many pharmacological effects through several neurotransmitter systems. In addition to binding to the N-methyl-d-aspartate (NMDA) subtype of the glutamate receptor, it also interferes with other brain functions. In this study, new derivatives (V – VII) were synthesized by changing aromatic moiety (phenyl, thienyl, and benzothiophene) and modifying cyclohexyl and piperidine rings (4-methylcyclohexyl and 3-piperidinol, respectively) of PCP. The acute and chronic pain activities of these new drugs were studied by using the tail immersion and formalin tests on mice and compared to control, PCP, and ketamine treated groups. The obtained results indicated that all new synthesized drugs showed better activity in decreasing acute thermal and chemical pains in tail immersion and formalin tests compared to PCP and ketamine. Also, compound VII (benzothiophene analog) produced more pronounced analgesic effects on acute thermal pain in tail immersion test, as well as compound V (thiophene analog)on acute chemical and chronic pains in formalin test as compared to other drugs.

Synthesis and Pain Perception of New Analogues of Phencyclidine in NMRI Male Mice

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

Pharmacology of Sigma (σ) Receptor Ligands from a Behavioral Perspective

The σ receptors are regarded as unique binding sites, distinct from opiate and PCP receptors and implicated in higher brain function. They were classified into σl and σ2 subtypes, the former was cloned from rodent and human tissues while the latter has not yet been fully characterized. Although the precise mechanism of the functional response of σ receptors is still uncertain, it has been accepted that they can modulate a number of central neurotransmitter systems, including glutamate/NMDA, serotonergic, dopaminergic, noradrenergic routes, as well as some other signaling pathways (e.g. neurotrophin and growth factor signaling) which are seemingly important for the brain function. In accordance with their modulatory role, σ receptor ligands have been proposed to be useful in several therapeutic areas such as schizophrenia, depression and anxiety, amnesic and cognitive deficits, drugs of abuse. The present review summarizes the findings related to the pharmacological effects and potential activity of σ receptor ligands from behavioral models predictive of some neuropsychiatric disorders.

Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABAAReceptors Containing α6 and δ Subunits

Phencyclidine (PCP) and ketamine are dissociative anesthetics capable of inducing analgesia, psychomimetic behavior, and a catatonic state of unconsciousness. Despite broad similarities, there are notable differences between the clinical actions of ketamine and PCP. Ketamine has a lower incidence of adverse effects and generally produces greater CNS depression than PCP. Both noncompetitively inhibit NMDA receptors, yet there is little evidence that these drugs affect GABA(A) receptors, the primary target of most anesthetics. alpha6beta2/3delta receptors are subtypes of the GABA(A) receptor family and are abundantly expressed in granular neurons within the adult cerebellum. Here, using an oocyte expression system, we show that at anesthetically relevant concentrations, ketamine, but not PCP, modulates alpha6beta2delta and alpha6beta3delta receptors. Additionally, at higher concentrations, ketamine directly activates these GABA(A) receptors. Comparatively, dizocilpine (MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate]), a potent noncompetitive antagonist of NMDA receptors that is structurally unrelated to PCP, did not produce any effect on alpha6beta2delta receptors. Of the recombinant GABA(A) receptor subtypes examined (alpha1beta2, alpha1beta2gamma2, alpha1beta2delta, alpha4beta2gamma2, alpha4beta2delta, alpha6beta2gamma2, alpha6beta2delta, and alpha6beta3delta), the actions of ketamine were unique to alpha6beta2delta and alpha6beta3delta receptors. In dissociated granule neurons and cerebellar slice recordings, ketamine potentiated the GABAergic conductance arising from alpha6-containing GABA(A) receptors, whereas PCP showed no effect. Furthermore, ketamine potentiation was absent in cerebellar granule neurons from transgenic functionally null alpha6(-/-) and delta(-/-)mice. These findings suggest that the higher CNS depressant level achieved by ketamine may be the result of its selective actions on alpha6beta2/3delta receptors.

Behavioral Pharmacology of σ-Ligands

Sigma (sigma) receptors, first defined as a subclass of opioid receptors, later confounded with the high affinity phencyclidine (PCP) binding sites, now are regarded as unique binding sites, distinct from opiate and PCP receptors, and related to higher brain function. The investigation of functional significance of sigma receptors in the brain has been hampered for many years by relative lack of specific tool drugs and by the unavailability of their coherent classification into postulated agonists and antagonists. However, a potential involvement of sigma receptors in psychotic disorders was first suggested soon after their discovery. The sigma receptors are classified into two subtypes, sigma (1) and sigma (2) receptors, of which the first was recently cloned from rodent and human tissues while the second has not yet been fully characterized. Although the precise mechanism of the functional response of these receptors is still uncertain, it is accepted that sigma receptors can modulate a number of central neurotransmitter systems, including noradrenergic, glutamatergic and dopaminergic ones. The sigma receptors have been postulated to be involved in numerous pharmacological and physiological functions, including motor disorders, psychotic disorders, neuroprotective mechanisms. In the last years, a number of compounds with a high affinity and selectivity for sigma binding sites have been discovered and investigated for their therapeutic potential. In this review, we try to summarize the behavioral effects of sigma receptor ligands that have been described, and their activity in animal models related to some brain disorders, especially schizophrenia and affective disorders.

Phencyclidine and dizocilpine modulate dopamine release from rat nucleus accumbens via σ receptors

Phencyclidine (PCP) binds to many sites in brain, including PCP receptors located within the N-methyl- d-aspartate (NMDA) receptor-operated cation channel and sigma (σ) receptors. In this study, we compare mechanisms by which PCP, dizocilpine (MK-801), the prototypical σ receptor agonist (+)-pentazocine, and the proposed endogenous σ receptor ligand neuropeptide Y regulate potassium (K +)-stimulated [ 3H]dopamine release from slices of rat nucleus accumbens. (+)-Pentazocine inhibits K +-stimulated [ 3H]dopamine release, and neuropeptide Y enhances it. Both effects are blocked by σ 1 and neuropeptide Y receptor antagonists, suggesting possible inverse agonism at a subpopulation of σ/neuropeptide Y receptors. In contrast, PCP and MK-801 both enhance K +-stimulated [ 3H]dopamine release via σ 1 and σ 2 receptor subtypes, as demonstrated by antagonist sensitivity. Regulation of release by both (+)-pentazocine and neuropeptide Y persists in the presence of tetrodotoxin suggests that the σ/neuropeptide Y receptors mediating the modulation are located presynaptically on dopaminergic nerve terminals, but tetrodotoxin eliminates regulation by PCP and MK-801, suggesting that receptors mediating their effects are located upstream from dopaminergic nerve terminals.

The search for TCP analogues binding to the low affinity PCP receptor sites in the rat cerebellum

With the aim of obtaining selective ligands of the low affinity binding sites of [ 3H]-1-[1-(2-thienyl)cyclohexyl]piperidine ([ 3H]TCP) in the rat cerebellum, oxygen and sulfur atoms were introduced in the TCP structure and derivatives to obtain analogues with a lowered lipophilicity. These compounds, and others already obtained, were assayed comparatively to determine their affinities for three sites labeled with [ 3H]TCP: one in the forebrain, the originally described PCP receptor, and two in the rat cerebellum. Lowering the lipophilicity and modifying the hetero-aromatic moiety yielded some ligands with increased affinity for the low affinity sites in the rat cerebellum and decreased affinity for the high affinity sites in the forebrain. Particularly, two compounds displaying both a high affinity and a good selectivity might be valuable tools to elucidate the pharmacology of the low affinity PCP sites labeled with [ 3H]TCP in the rat cerebellum.

Effect of PCP and sigma ligands on both noradrenaline- and electrically-induced contractions and on [3H]-noradrenaline uptake in rat vas deferens.

1. Electrically induced contractions of the epididymal portion of rat vas deferens were potentiated in concentration-dependent manner (0.1-30 microM) by different sigma and PCP receptor ligands (PCP, TCP, (+)-MK-801, dextromethorphan and (+)-3-PPP); dextrorphan did it in a minor extent. 2. Sigma and PCP receptor ligands also potentiated the effect of noradrenaline, inducing a reduction of the noradrenaline EC50 value in the rat vas deferens. The rank order of potencies was: PCP > TCP > (+)-3-PPP > (+)-MK-801 > dextrorphan > > > dextrometorphan. 3. In contrast, haloperidol (1 microM), a sigma receptor ligand, inhibited both the neurogenic and noradrenaline-induced responses in this tissue. 4. The effect of PCP and sigma receptor ligands on noradrenaline uptake was evaluated. All compounds tested, including haloperidol, inhibited the tritiated noradrenaline incorporation to the tissue. IC50 values were in the micromolar range, between 1.09 microM for dextrophan and 18 microM for dextrometorphan. 5. It is concluded that a direct interaction with the noradrenaline uptake system is involved in the potentiating effect of some sigma and PCP receptor ligands in the epididymal portion of rat vas deferens.

The Effects of Sigma, PCP, and Opiate Receptor Ligands in Rats Trained With Ibogaine as a Discriminative Stimulus

HELSLEY, S., R. FILIPINK, W. D. BOWEN, R. A. RABIN AND J. C. WINTER. Interactions of sigma, PCP, and opiate ligands with the ibogaine-induced discriminative stimulus. PHARMACOL BIOCHEM BEHAV 59(2) 495–503, 1998.–Although the mechanism of action of ibogaine, a hallucinogen that may be useful in the treatment of addiction, remains unknown, receptor binding studies suggest that ibogaine produces its effects via interactions with multiple receptor types. In addition to serotonergic receptors, which have been studied previously with respect to ibogaine, likely candidates include opiate, sigma (σ), and phencyclidine (PCP) binding sites. In an attempt to determine which of these receptor interactions are involved in the in vivo effects of ibogaine, ligands for σ, PCP, and opiate receptors were assessed for their ability to substitute for or to antagonize the ibogaine-induced discriminative stimulus (10 mg/kg IP, 60 min presession) in Fischer-344 rats. Intermediate levels of generalization were observed with the subtype nonselective σ ligands 3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-PPP] (69.0%) and 1,3-di(2-tolyl)guanidine (DTG) (73.5%) but not with the σ 1-selective agents (+)-N-allylnormetazocine [(+)-SKF 10,047] and (+)-pentazocine. These findings, along with observations that ibogaine has appreciable affinity for σ 2 receptors, suggest that these receptors may be involved in the ibogaine discriminative stimulus. With regard to opiate receptors, neither morphine, the prototypic mu agonist, nor kappa selective agonists (bremazocine,and U-50488) substituted for ibogaine. However, intermediate levels of generalization were observed with the mixed action opiates (−)-SKF 10,047 (78.9%), (±)-pentazocine (73.9%), nalorphine (70.4%), and diprenorphine (75.0%) indicating a potential role for opiate receptors in the ibogaine stimulus. Partial substitution was also observed with naltrexone (55.6%) but not with naloxone or the selective kappa antagonist nor-binaltorphimine (nor-BNI). These agents were largely ineffective as antagonists of the ibogaine cue, although naloxone produced a moderate but statistically significant antagonism (69.8%). In addition, naloxone produced complete antagonism of the ibogaine-appropriate responding elicited by both (−)-SKF 10,047 (19.7%) and nalorphine (25.8%), whereas the ibogaine-appropriate responding produced by diprenorphine was only partially antagonized (44.4%). The latter observations taken together with the finding that both nalorphine (>100 μM) and diprenorphine (30 μM) have extremely low affinity for σ 2 receptors, suggest that the ibogaine-appropriate responding produced by these agents is not mediated by σ 2 receptors. These findings imply that opiate effects may be involved in the ibogaine stimulus. In contrast to σ 2 and opiate receptors, ibogaine’s reported interactions with NMDA receptors do not appear to be involved in its discriminative stimulus, as neither PCP nor MK-801 produced a significant level of ibogaine-appropriate responding. Thus, the present study offers evidence that unlike NMDA receptors, both σ 2 and opiate receptors may be involved in the ibogaine discriminative stimulus.

Rigid Phencyclidine Analogues. Binding to the Phencyclidine and σ1 Receptors

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.

Sensitivity of the PCP receptor and the dopamine transporter to ligands bearing multiple asymmetric centres

Summary Generation of one or two asymmetric carbons by means of a methyl substitution into cyclohexyl or piperidine moieties of 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) and 1-[1-(2-benzo[ b ]thiophenyl)cyclohexyl]piperidine (BTCP) structures has revealed improved affinity and/or selectivity for the PCP receptor and the dopamine (DA) transporter, respectively. Therefore, to get more information about the influence of chiral centres on affinity and selectivity, simultaneous methyl substitutions of cyclohexyl and piperidine moieties have been performed to generate three asymmetric carbons into the parent structures. Thus, cis -(Pip/Me)-1-[1-(2-thienyl)-2-methylcyclohexyl]-3-methylpiperidines and cis -(Pip/Me)-1-[1-(2-benzo[ b ]thiophenyl)-2-methylcyclohexyl]-3-methylpiperidines in homochiral forms have been prepared and their affinities for the PCP receptor ([ 3 H]TCP binding) and for the DA transporter ([ 3 H]BTCP binding) have been measured on rat brain and striatal membranes, respectively. None of the enantiomeric structures revealed affinities and/or selectivities in the same range as molecules bearing one or two asymmetric centres. In the TCP series the best compounds were in the same range as the parent compound. In the BTCP series, pure stereomers displayed lowered affinities and considerably reduced selectivities than the parent compound.

New sigma and 5-HT1A receptor ligands: omega-(tetralin-1-yl)-n-alkylamine derivatives.

Two series of compounds that are structurally related to benzomorphans, derived by structural modification of arylpiperazines with high 5-HT1A affinity and moderate sigma affinity, were prepared in order to increase sigma affinity and selectivity. All new compounds are N-substituted-omega-(1,2,3,4-tetrahydronaphthalen-1-yl)- or -omega-(1,2-dihydronaphthalen-4-yl)-n-alkylamines with, in some cases, a methoxy group on the tetralin moiety. They were tested in radioligand binding assays on sigma ([3H]DTG and [3H]-(+)-pentazocine), D-2 dopaminergic, 5-HT1A and 5-HT2 serotonergic, and PCP (phencyclidine) receptors. A first set of compounds bearing a 4-(1-substituted)piperazine moiety as terminal fragment on the alkyl chain showed moderate to high sigma affinity (Ki = 5.3-139 nM), the most active and selective being 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n- propyl ]piperazine (14), with probable pronounced sigma 2 affinity (Ki = 5.3 nM on [3H]DTG and Ki = 71 nM on [3H]-(+)-pentazocine). Moreover, compound 13, a 1-benzylpiperazine analogue of 14, preserved a dual high 5-HT1A and sigma affinity (Ki = 3.6 nM on [3H]-5-HT and Ki = 7.0 nM on [3H]DTG). The second set of compounds includes some N-phenylalkyl derivatives of 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)- n-propylamine that can be considered to be open-chain derivatives of 4-substituted-1-arylpiperazines. Among these compounds that had a lower activity toward sigma binding sites, a high 5-HT1A affinity was found for the N-(3-phenylpropyl) derivative 21 (Ki = 4.4 nM) which demonstrated very good selectivity.

Effect of lowered lipophilicity on the affinity of PCP analogues for the PCP receptor and the dopamine transporter

Summary Oxygen and sulphur atoms were introduced in the cyclohcxyl and piperidinyl moieties of the basic structures 1-(1-phenyl-cyclohexyl)piperidine (PCP), 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), and 1-[1-(2-benzo[ b ]thiophenyl)cyclohexyl]piperidine (BTCP) to lower their global lipophilicity. The compounds obtained were tested comparatively for their affinity for the PCP receptor labelled with [ 3 H]TCP and for the dopamine (DA) transporter labelled with [ 3 H]BTCP. Lowering the global lipophilicity in PCP and TCP series is detrimental to the affinity and selectivity for the PCP receptor. In the BTCP series lowering of the global lipophilicity is less deleterious and may, on the contrary, be a useful way of increasing selectivity for the DA transporter in some instances.

Functional and binding properties of sigma receptors in rat cerebellum.

Autoradiographic studies have shown that sigma receptors are enriched in the locus coeruleus, the origin of noradrenergic projections to the cerebellum, as well as in the Purkinje, molecular, and granular layers and the interpositus cerebellar nucleus of the cerebellum itself. In contrast, the cerebellum is relatively poor in phencyclidine (PCP) binding sites, which have been historically confused with sigma sites. The high ratio of sigma to PCP receptors in cerebellum is advantageous for discriminating sigma-mediated physiological effects. sigma agonists and antagonists have been shown to regulate N-methyl-D-aspartate (NMDA)-stimulated norepinephrine release in hippocampus, which is innervated by locus coeruleus projections. We now report that sigma drugs also regulate norepinephrine release from cerebellum. In contrast to findings in the hippocampus, where regulation is via sigma 1 and sigma 2 receptors, sigma-mediated regulation in cerebellum seems to be primarily via sigma 1 receptors. In radioligand binding studies, we find that sigma receptors primarily of the sigma 1 type are present in the cerebellum. We further report that binding to sigma receptors in cerebellum is not affected by the addition of NMDA or glycine or by the presence of NMDA antagonists, suggesting that sigma receptors are not located within the NMDA-operated cation channel in this brain region.

3H]MK-801 binding to well-washed rat brain membranes following cessation of chronic phencyclidine treatment

Rats were implanted with osmotic minipumps SC that infused either saline or 10 mg/kg/day phencyclidine (PCP) for 10 days, a regimen that produces dependence to PCP. At the end of this 10-day infusion period, the pumps were removed and the rats were sacrificed either immediately or at various time points (12 h, 1, 2, and 7 days) after pump removal. The saturation binding parameters of [ 3H]MK-801 were then determined in well-washed cortical/hippocampal membranes prepared from these rats. Neither the B max nor the K d of [ 3H]MK-801 binding in membranes of PCP-treated rats differed from that determined using membranes from saline-treated rats at any time point studied. These results suggest that alterations in PCP receptors do not play a major role in the production of PCP dependence.

Synthesis and evaluation of 6,11-ethanohexahydrobenzo[b]quinolizidines: a new class of noncompetitive N-methyl-D-aspartate antagonists.

The synthesis and in vitro and in vivo evaluation of 12,13-cycloalkyl-6,11-ethanobenzo[b]-quinolizidines, a new class of noncompetitive N-methyl-D-aspartate (NMDA) antagonists acting at the PCP site on the NMDA receptor complex, is reported. Structure-activity relationship studies led to the identification of 10-hydroxy-(6 alpha,11 alpha,11 alpha beta,12R*,13S*)-1,3,4,6,11,11a,13,14,15,16-decahydro-12H- 6,11[1',2']-endo-cyclopenta-2H-pyrido[1,2-b]isoquinoline hydrobromide (5h) and 9-hydroxy-(6 alpha,11 alpha,11a beta,12R*,13S*)- 1,3,4,6,11,11a,13,14,15,16-decahydro-12H-6,11-[1',2']-endo-cycl ope nta-2H- pyrido[1,2-b]isoquinoline hydrobromide (5i), the most potent members of this series with Ki values of 2.3 +/- 0.2 and 2.3 +/- 0.5 nM, respectively. Molecular modeling studies revealed that this series of compounds occupies both lipophilic sites of the Andrews PCP receptor model and shares structural features which are common to other classes of known noncompetitive NMDA antagonists such as MK-801.

Auditory ERPs in schizophrenia: Diagnostic and symptom correlates

ceived one dose of MK801 (0.05, 0.1 or 0.5 mg/kg) and saline in a counterbalanced design (l week between tests). Thirty minutes after injection, animals were exposed to 5 minutes background noise (70 dB) followed by 5 types of startle stimuli (total of 111 trials): startle pulse alone (PA, 116 dB, 30 msec duration), and PA preceded by inhibitory prepulses (75, 80, or 85 dB, 30 msec duration), or by a facilitatory prepulse (73 dB, 10 msec duration). Baseline startle, percent inhibition/facilitation, and within session habituation were calculated. Complete disruption of PPI for all inhibitory trials occurred at the two higher doses of MK-801. Baseline amplitude and PPF were enhanced by low-dnse MK-801 but reduced by higher doses, and habituation of ASR was impaired by the higher doses. These findings further support the involvement of PCP or NMDA receptors in the modulation of sensory gating and suggest that unique sensory gating abnormalities result from NMDA antagonists and DA agonists. Similar patterns, if present in subgroups of schizophrenia patients, would provide indirect evidence for DA hyperactivity vs. hypoglutamatergia. Such differentiation could further our understanding of the pathophysiology and treatment resl:xmse of schizophrenic patients. (Supported by MH00859.)