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At least 19 recordsLinked to original sources
PubMed1987

Guinea-pig vas deferens preparation may contain both receptors and phencyclidine receptors.

Electrically induced contractions of guinea-pig vas deferens were potentiated by sigma drugs such as d-pentazocine and d-SKF-10047 and also by phencyclidine-like drugs. Non-sigma drugs like morphine, buprenorphine, DADLE, U-50488 and l-ketocyclazocine did not potentiate contractions. The potentiations were antagonized by haloperidol and BW234U. Although the potentiation may not be definitively mediated by sigma receptors or phencyclidine receptors alone, the preparation may provide an interesting tool for studying endogenous ligands which might act like sigma or phencyclidine drugs.

Animals↗
PubMed1986

Metaphit, a proposed phencyclidine receptor acylator: phencyclidine-like behavioral effects and evidence of absence of antagonist activity in pigeons and in rhesus monkeys.

Metaphit, a derivative of phencyclidine (PCP), binds irreversibly to PCP sites and appears to act as an antagonist of PCP under some conditions and as a PCP-like agonist under other conditions. To describe further these conditions, the authors investigated the behavioral effects of metaphit by using different routes of administration, behavioral procedures and species. In pigeons, metaphit induced PCP-like catalepsy after i.c.v. administration and, after i.m. administration, produced PCP-like discriminative stimulus effects and stereotyped operant responding. In rhesus monkeys, metaphit produced ataxia and convulsions but did not induce catalepsy, anesthesia or PCP-like discriminative stimulus effects. None of the effects of PCP-type drugs [i.e., PCP, ketamine or (+/-)-SKF 10,047] in pigeons or rhesus monkeys was antagonized by metaphit. Metaphit potentiated the discriminative stimulus effects of PCP and of SKF 10,047 in pigeons. These results suggest that metaphit acts not as an antagonist of PCP but as a PCP-like agonist under these conditions. Metaphit's potentiation of behavioral effects of PCP may be related to the presumed ability of metaphit to acylate PCP receptors. The extent to which metaphit produces PCP-like behavioral effects in part may be species dependent.

Acylation↗
PubMed1988

Solubilization of rat brain phencyclidine receptors in an active binding form that is sensitive to N-methyl-D-aspartate receptor ligands.

Phencyclidine (PCP) receptors were successfully solubilized from rat forebrain membranes with 1% sodium cholate. Approximately 58% of the initial protein and 20-30% of the high-affinity PCP binding sites were solubilized. The high affinity toward PCP-like drugs, the stereo-selectivity of the sites, and the sensitivity to N-methyl-D-aspartate (NMDA) receptor ligands were preserved. Binding of the potent PCP receptor ligand N-[3H][1-(2-thienyl)cyclohexyl] piperidine ([3H]TCP) to the soluble receptors was saturable (KD = 35 nM), and PCP-like drugs inhibited [3H]TCP binding in a rank order of potency close to that observed for the membrane-bound receptors; the most potent inhibitors were TCP (Ki = 31 nM) and the anticonvulsant MK-801 (Ki = 50 nM). The NMDA receptor antagonist 2-amino-5-phosphonovaleric acid inhibited binding of [3H]TCP to the soluble receptors; glutamate or NMDA diminished this inhibition in a dose-dependent manner. Taken together, the results indicate that the soluble PCP receptor preparation contains the glutamate recognition sites and may represent a single receptor complex for PCP and NMDA, as suggested by electrophysiological data. The successful solubilization of the PCP receptors in an active binding form should now facilitate their purification.

2-Amino-5-phosphonovalerate↗
PubMed1986

Stereotyped behavior correlates better than ataxia with phencyclidine-receptor interactions.

The interaction of phencyclidine, dexoxadrol, their analogs and stereoisomers with phencyclidine receptors was compared to their ability to induce stereotyped behavior and ataxia after i.c.v. administration to rats. The order of potency for binding to phencyclidine receptors revealed that among the stereoisomers of phencyclidine derivatives, the (+) isomer was more potent than the (-) isomer. A similar order of potency of phencyclidine derivatives and degree of stereoselectivity was seen in the assays for stereotyped behavior and phencyclidine receptor interactions, which resulted in a good correlation between the relative potencies for binding to phencyclidine receptors and inducing stereotyped behavior. However, the order of potency for induction of ataxia and the stereoselectivity was different than that seen in the assays for phencyclidine receptor interactions and stereotyped behavior. A comparison of relative potencies for binding to phencyclidine receptors to induction of ataxia still resulted in a good fit to a straight line, but the line did not intersect the origin, indicating that a non-phencyclidine receptor component is also involved in mediating ataxia. Dextrorphan and 2-methyl-3,3-diphenyl-3-propylamine were equipotent as phencyclidine in phencyclidine receptor and behavioral assays. The order of potency for interacting with phencyclidine receptors and inducing phencyclidine-like behavior by the isomers of cyclazocine were opposite to that of other phencyclidine analogs. Also, the order of potency for induction of ataxia by the isomers of N-allylnormetazocine was opposite to that for phencyclidine receptor interactions. Ethylketocyclazocine did not induce any stereotyped behavior or ataxia, indicating that it is unlikely that a kappa opioid receptor interaction plays a role in mediating ataxia. Furthermore, stereotyped behavior and ataxia were not due to interactions with mu, kappa or delta opioid receptors as naloxone did not antagonize the behavioral effects of phencyclidine, (-)cyclazocine or (-)N-allylnormetazocine. These results indicate that stereotyped behavior is mediated by phencyclidine receptors, whereas ataxia is mediated by more than just phencyclidine receptors.

Animals↗
PubMed1987

Synthesis and characterization of an affinity label for brain receptors to psychotomimetic benzomorphans: differentiation of sigma-type and phencyclidine receptors.

Brain sigma-type receptors and phencyclidine receptors are thought to mediate the psychotomimetic effects of benzomorphans and phencyclidine in humans. Recently, we reported the characterization of a selective sigma receptor ligand, 1,3-di-o-tolyl-guanidine (DTG), that shows negligible crossreactivity with phencyclidine receptors. Here we describe the synthesis and characterization of an isothiocyanate derivative of DTG, di-o-tolyl-guanidine-isothiocyanate (DIGIT). Guinea pig brain membranes treated with nanomolar doses of DIGIT followed by extensive washing exhibit a dose dependent reduction of [3H]DTG and (+)[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [+)[3H]3-PPP) binding to sigma receptors. Binding of radiolabelled ligands for phencyclidine, mu-opioid, benzodiazepine and dopamine-D2 receptors is not affected by membrane treatment with DIGIT, indicating specificity of the affinity label for sigma-type receptors. Treatment of DIGIT-derivatized membranes with 2 M NaCl does not result in recovery of sigma binding activity, suggesting that DIGIT's interaction with sigma receptors is not of an ionic nature. Equilibrium saturation binding experiments show that the inhibition of [3H]DTG binding to sigma receptors by DIGIT pretreatment of membranes is attributable to an irreversible reduction in the affinity (increase in Kd) of sigma receptors for DTG. The finding that sigma receptors are irreversibly modified by DIGIT whereas phencyclidine receptors are not affected suggests that sigma receptors are physically separate from phencyclidine receptors. The availability of a selective affinity label for the sigma receptor should facilitate the purification of the receptors and the characterization of sigma-type pharmacological effects in vivo and in vitro.

Affinity Labels↗
PubMed1990

Guinea pig vas deferens contains sigma but not phencyclidine receptors.

Homogenates from guinea pig vas deferens were examined for possible existence of sigma receptor and phencyclidine (PCP) receptor using a radioligand binding assay. [3H](+)-SKF-10047 bound saturably in the homogenates to a single population of binding sites with a Kd of 311 and a Bmax of 1090 fmol/mg protein. IC50S of several representative sigma in displacing [3H](+)-SKF-10047 from this binding site were very much similar to the IC50S of those drugs in the brain sigma receptor binding assay. A correlation coefficient of 0.96 was obtained when IC50S from vas deferens were compared with those from the brain assay. Attempts to demonstrate PCP receptors in this tissue using [3H]TCP (N-[1-(2-thienyl)cyclohexyl]piperidine), however, yielded negative results. The results indicate that while guinea pig vas deferens contains sigma receptors, PCP receptors may be absent in this tissue.

Animals↗
PubMed1985

Sigma opioid receptor: characterization and co-identity with the phencyclidine receptor.

The properties of the sigma opioid receptor of rat brain cortex have been characterized using the prototypic ligand (+)-[3H] SKF 10,047. Binding to this receptor was rapid, and equilibrium was obtained within 30 min at 37 degrees C. Specific binding was linear with protein concentration up to 500 micrograms/2 ml and was dependent upon protein integrity. Denaturation by boiling destroyed over 95% of the specific binding. A high-affinity binding site with a KD of 150 +/- 40 nM and a maximum binding of 2.91 +/- 0.84 pmol/mg of protein was determined from a Scatchard plot of the binding data. The addition of salt, either NaCl or CaCl2, to the buffers markedly decreased binding, with CaCl2 being more potent than NaCl. A broad pH optimum for specific binding was observed; maximum binding was at pH 9.0. The affinity of a number of ligands for the sigma site and the phencyclidine receptor were compared. The binding (IC50) of 13 ligands to the sigma site showed a correlation of 0.86 (P less than .01) with binding to the phencyclidine site. The data demonstrate that the biochemical properties of the sigma and phencyclidine receptors are similar and support the view that these receptors are one and the same site.

Animals↗
PubMed1994

Activation-related and activation-independent effects of polyamines on phencyclidine receptor binding within the N-methyl-D-aspartate receptor complex.

The phencyclidine (PCP) receptor is located within the N-methyl-D-aspartate (NMDA) receptor-gated ion channel. The functional state of the NMDA receptor complex thus influences parameters of radioligand binding to the PCP receptor, and PCP receptor ligands can serve as in vitro probes for elucidation of NMDA receptor activation mechanisms. PCP receptor binding is stimulated by NMDA receptor agonists such as L-glutamate and also by distinct classes of modulatory agents such as glycine-like amino acids and polyamines such as spermidine (SPD). The present study utilizes a kinetic approach permitting differentiation of PCP receptor binding within closed and activated conformations of the NMDA receptor complex. The results demonstrate that SPD increases radioligand binding to the PCP receptor through two distinct mechanisms. First, SPD, like glycine, increases the percentage of time that NMDA channels remain in the open state in the presence of L-glutamate, consistent with a role as a positive allosteric modulator of NMDA receptor activation. Second, unlike glycine, SPD increases the affinity of the PCP receptor for its ligands. The latter effect does not appear to reflect increased NMDA receptor activation. SPD does not induce glycine-like alteration of the EC50 value for stimulation of PCP receptor binding by L-glutamate, suggesting that the effects of SPD cannot be attributed solely to augmentation of glycine binding. These findings demonstrate first that total specific PCP receptor binding cannot, of itself, be used as an index of NMDA receptor activation and second, glycine and polyamines differ in the mechanisms by which they potentiate PCP receptor binding.

Animals↗
PubMed1989

Phencyclidine suppresses hippocampal long-term potentiation through stereospecific activation of phencyclidine receptors.

The effects of phencyclidine and the dioxolane enantiomers, dexoxadrol and levoxadrol, on long-term potentiation in the hippocampus were compared. Field potentials were evoked by stimulation of Schaffer collaterals and recorded from the CA1 region. Long-term potentiation was induced by stimulation with a single train of 25 pulses at 50 Hz. The drugs were delivered by pressure, 1 min before tetanization. Phencyclidine and its receptors ligand, dexoxadrol, abolished the induction of long-term potentiation. Levoxadrol which has very low affinity for the phencyclidine receptor was devoid of this action although it reduced the magnitude of long-term potentiation. These results indicate that phencyclidine blocks long-term potentiation by stereospecific activation of phencyclidine receptors.

Analgesics↗
PubMed1991

Interactions of sigma and phencyclidine receptor ligands with the norepinephrine uptake carrier in both rat brain and rat tail artery.

The interaction of several sigma and PCP receptor ligands with the norepinephrine uptake carrier was investigated in the rat tail artery and brain. These ligands include haloperidol; (+)- and (-) 3-(3-hydroxy- phenyl)-N-(1-propyl)piperidine (3-PPP), (+/-)-BMY 14802, [(+/-) alpha-(4-fluoro- phenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol]; (+)-SKF 10047, [(+/-)-N-allyl-N-normetazocine]; 1,3-di-ortho-tolyl-guanidine; rimcazole (BW 234U), [cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl] carbazole dihydrochloride]; and MK 801, [(+)-5-methyl-10,1 1-dihydro-5H-dibenzo[a, d]cyclohepten-5, 10-imine maleate]. Our results show that all ligands used, except 1,3-di-ortho-tolyl-guanidine, inhibit both neuronal [3H]norepinephrine accumulation in the rat tail artery and specific [3H] desmethylimipramine binding in the rat brain. Except for (+)-SKF 10047, the order of potency of the ligands used for inhibiting neuronal [3H]norepinephrine accumulation in the rat tail artery was similar to that measured for inhibition of specific [3H]desmethylimipramine binding in the rat brain. Despite these similarities, our results also suggest that haloperidol, (+)- and (-)3-PPP, MK 801, rimcazole and cocaine interact with the [3H]norepinephrine site in the rat tail artery and with the [3H]desmethylimipramine binding site in the rat brain in a complex fashion. These studies demonstrate an important action on the norepinephrine carrier by these sigma and PCP ligands in the rat tail artery and brain.

Animals↗
PubMed1985

A specific acylating agent for the [3H]phencyclidine receptors in rat brain.

A derivative of phencyclidine (PCP, 1 in fig. 1) bearing an isothiocyanate moiety on the meta position of the aromatic ring (Metaphit, 3 in fig. 1) has been synthesized and identified as a rapid and specific site-directed acylating agent of the [3H]phencyclidine binding site in rat brain homogenates. The percentage of sites irreversibly inactivated by Metaphit was found to be the same in the hippocampus and striatum and the remaining sites were unaffected by Metaphit treatment under any conditions, suggesting that at least two distinct binding sites are present. An isomeric isothiocyanate derivative did not irreversibly inhibit [3H]phencyclidine receptors, indicating structural specificity for Metaphit in the inhibition of these receptors. The availability of Metaphit should greatly facilitate study of the structure and function of the phencyclidine receptors.

Acylation↗
PubMed1989

[Adaptive changes in sigma and phencyclidine receptors during the long-term use of haloperidol and raclopride in rats].

The experiments on male albino rats have shown that 15 days haloperidol (0.5 mg/kg) and raclopride (1 mg/kg) treatment, but not acute administration, causes the increase of density of sigma receptors in the brain. The number of phencyclidine receptors was also elevated, but this increase was not statistically evident. The behavioral effects of ketamine (5 mg/kg) were evidently decreased after long-term haloperidol and raclopride treatment. The motor stimulation and stereotyped behavior induced by apomorphine (0.15 mg/kg) were increased only after treatment of haloperidol, but not raclopride. It seems probable that repeated neuroleptic (haloperidol and raclopride) treatment causes the hyposensitivity of sigma and phencyclidine receptors, despite the increase of their number. It is possible that this change is related to the depolarization inactivation of dopamine neurons caused by repeated neuroleptic administration.

Adaptation, Physiological↗
PubMed1990

Pharmacological characteristics and distributions of sigma- and phencyclidine receptors in the animal kingdom.

The phylogenetic distributions of sigma- and phencyclidine receptors in neural tissues of 13 species and the pharmacological characteristics of these receptors in whole sea anemone and neural tissues of the guinea pig, chicken, and frog were studied. Specific binding of [3H]haloperidol and [3H]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine, ligands that bind with high affinity to sigma- and phencyclidine receptors, respectively, was detected in all organisms examined. The order of potencies of various ligands to inhibit 1 nM [3H]haloperidol binding in brains of frogs and guinea pigs or 1 nM [3H]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine in chicken or guinea pig brain homogenates was very similar. However, the characteristics and stereospecificity of binding of the two radioligands in sea anemone were different than in higher organisms. The results suggest that sigma- and phencyclidine binding sites are evolutionarily old, as the characteristics of the two sites are well preserved over a range of vertebrate phyla.

Animals↗
PubMed1989

Electrophysiological effects of selective sigma-receptor agonists, antagonists, and the selective phencyclidine receptor agonist MK-801 on midbrain dopamine neurons.

Extracellular single unit recording techniques were used to study the effects of selective sigma-receptor agonist [(+)-3-PPP, (+)-pentazocine, and DTG] and selective sigma-receptor antagonists (BMY 14802 and Rimcazole) on dopamine neurons of the substantia nigra. Intravenous (IV) administration of sigma agonists decreased, whereas IV administration of the sigma antagonist BMY-14802 increased the firing rate of dopamine neurons. The other sigma antagonist Rimcazole produced inconsistent changes in dopamine unit activity. These data, in conjunction with anatomic data suggesting sigma receptor localization on dopamine neurons in the substantia nigra (Gundlach et al: J Neurosci 6:1757-1770, 1986; Graybiel et al: Soc Neurosci Abstr 13:28, 1987) demonstrate a relationship of the sigma receptor with the dopamine system and further suggest a model system to study agonist-antagonist interactions of sigma ligands. The selective phencyclidine (PCP) agonist MK-801 was equipotent to PCP in regard to stimulatory properties on dopamine neurons. However, the relative potencies do not correspond to their relative binding affinities, suggesting that non-PCP-receptor properties may mediate this effect.

Animals↗
PubMed1991

Binding affinity and antimuscarinic activity of sigma and phencyclidine receptor ligands.

The characterization of the sigma receptor has been hampered by the lack of a functional bioassay system. Drugs that bind to sigma receptors have been reported to inhibit carbachol-induced phosphatidylinositol turnover in rat brain; however, these drugs might directly affect muscarinic acetylcholine receptors. The purpose of the present study was to determine the affinity for muscarinic receptors and the antimuscarinic activity of sigma and phencyclidine receptor ligands. All of the drugs tested inhibited the binding of [3H]N-methylscopolamine to guinea pig cerebral cortical membranes with KI values in the micromolar range and also inhibited carbachol-induced contractions in the guinea pig ileum. These results demonstrate that these compounds have substantial antimuscarinic activity which might limit the use of the inhibition of carbachol-induced phosphatidylinositol turnover as a functional assay system for studying sigma ligands. Furthermore, this antimuscarinic activity must be considered when evaluating the effects of these compounds after in vivo administration.

Animals↗
PubMed1986

An endogenous ligand for phencyclidine receptors: isolated from human brains.

Using preparative HPLC, Sephadex G-25 and analytic HPLC, we obtained an active peak inhibiting (3H) PCP receptor binding, with a molecular weight of 3,000 daltons. Another isolation process included acetic acid extraction, Toyopearl HW gel filtration, Sephadex G-10 chromatography and analytic HPLC. An active peak was also observed, which was consistent with that from the first isolation process.

Brain↗
PubMed1986

An endogenous ligand from human CSE for the phencyclidine receptor.

A fraction which potently and specifically competed with 3H-PCP binding to rat membranes was isolated from human CSF. This substance ran just before the salts in Sephadex G-25 column and was eluted with low concentrations of acetonitrile in reverse phase HPLC, predicating that it may be a small hydrophilic compound with a MW. of less than 1,000 daltons.

Animals↗