Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies from our laboratory have provided evidence that multiple states of the phencyclidine (PCP) receptor exist. In addition, several compounds such as PCP and the novel anticonvulsant MK-801 were found to inhibit binding more potently in the presence of Mg2+ and L-glutamate (L-GLU) than when these agents were excluded from the binding assay. In the present study, a number of pharmacological compounds that have been suggested to interact within the N-methyl-D-aspartate (NMDA) receptor complex, including tricyclic antidepressants (TCAs), were examined for their ability to inhibit the binding of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine [( 3H]TCP) in the absence or presence of Mg2+ and L-GLU. The TCAs imipramine, amitriptyline, and opipramol produced shallow inhibition curves in the absence of Mg2+ and L-GLU. Computer analysis of the binding data indicated that a two-component binding model described the data significantly better than a one-component model. In the presence of Mg2+ and L-GLU, the inhibition curves became steeper and were shifted to the right, and computer analysis of the binding data indicated that a one-component model adequately described the binding data. A series of other centrally active compounds, including several antipsychotics and antihistamines, the antiparkinsonian anticholinergic trihexyphenidyl and the antitussive dextromethorphan, were also found to be affected similarly by the inclusion of Mg2+ and L-GLU in the binding assay. Dextrorphan, in contrast to dextromethorphan, inhibited [3H]TCP binding more potently in the presence of Mg2+ and L-GLU. The present results suggest that the compounds that inhibit binding more potently in the absence of Mg2+ and L-GLU are interacting with the PCP receptor in a different manner from that of PCP and MK-801, because these open-channel blockers inhibit [3H]TCP binding more potently in the presence of Mg2+ and L-GLU. The data support previous findings that TCAs interact with the NMDA receptor complex and suggest that the compounds trihexyphenidyl and dextromethorphan, which have been shown to block NMDA-mediated neurotoxicity, may produce their effects through an interaction with the PCP receptor, albeit by a different mechanism from that of open-channel blockers.
Mol Pharmacol 1989 Jul
PMID:Tricyclic antidepressants and dextromethorphan bind with higher affinity to the phencyclidine receptor in the absence of magnesium and L-glutamate. 256 80

Opioid, sigma, and phencyclidine (PCP) receptors were characterized in the mouse neuroblastoma--Chinese hamster brain hybrid cell line NCB-20. Quantitative receptor assays under equilibrium binding conditions with highly specific radioligands demonstrated the presence of delta, but not mu or kappa, opioid receptors on NCB-20 cell membranes. NCB-20 cells were shown to possess two distinct sites specific for sigma opioids and PCP derivatives. One site was labeled by (+)-[3H]N-allylnormetazocine [(+)-[3H]SKF-10,047] (Kd = 69 nM; Bmax = 4100 fmol/mg of protein). The rank order of potency of drugs at this site was (+)-3-(3-hydroxy-phenyl)-N-(1-propyl)piperidine [(+)-3-PPP] greater than haloperidol greater than (+)-SKF-10,047 greater than (+/-)-ethylketocyclazocine greater than (+/-)-bremazocine greater than N-[1-(2-thienyl) cyclohexyl]piperidine (TCP) greater than dexoxadrol. This site is similar in its ligand selectivity to the haloperidol-sensitive sigma receptor of rat brain. The other site was labeled by the potent phencyclidine derivative [3H]TCP (Kd = 335 nM; Bmax = 9300 fmol/mg of protein). This density is equivalent to approximately 60,000 sites/cell. The rank order of potency of drugs at this site was TCP greater than (+)-3-PPP greater than PCP greater than dexoxadrol greater than haloperidol greater than cyclazocine greater than levoxadrol greater than (+)-SKF-10,047; mu and delta ligands were inactive. This site is similar to the rat brain PCP receptor. The NCB-20 cell line is the only cultured cell line that has been demonstrated to have PCP receptors.
Mol Pharmacol 1988 Nov
PMID:Characterization of opioid, sigma, and phencyclidine receptors in the neuroblastoma-brain hybrid cell line NCB-20. 284 88

Computer-assisted molecular modelling techniques and electrostatic analyses of a wide range of phenycyclidine (PCP) and sigma ligands, in conjunction with radioreceptor studies, were used to determine the topographies of the PCP and sigma receptors. The PCP receptor model was defined using key molecules from the arylcyclohexylamine, benzomorphan, bridged benz[f]isoquinoline, and dibenzocycloalkenimine drug classes. Hypothetical receptor points (R1, R2) were constructed onto the aromatic ring of each compound to represent hydrophobic interactions with the receptor, along with an additional receptor point (R3) representing a hydrogen bond between the nitrogen atom and the receptor. The superimposition of these key molecules gave the coordinates of the receptor points and nitrogen defining the primary PCP pharmacophore as follows: R1 (0.00, 3.50, 0.00), R2 (0.00, -3.50, 0.00), R3 (6.66, -1.13, 0.00), and N (3.90, -1.46, -0.32). Additional analyses were used to describe secondary binding sites for an additional hydrogen bonding site and two lipophilic clefts. Similarly, the sigma receptor model was constructed from ligands of the benzomorphan, octahydrobenzo[f]quinoline, phenylpiperidine, and diphenylguanidine drug classes. Coordinates for the primary sigma pharmacophore are as follows: R1 (0.00, 3.50, 0.00), R2 (0.00, -3.50, 0.00), R3 (6.09, 2.09, 0.00), and N (4.9, -0.12, -1.25). Secondary binding sites for sigma ligands were proposed for the interaction of aromatic ring substituents and large N-substituted lipophilic groups with the receptor. The sigma receptor model differs from the PCP model in the position of nitrogen atom, direction of the nitrogen lone pair vector, and secondary sigma binding sites. This study has thus demonstrated that the differing quantitative structure-activity relationships of PCP and sigma ligands allow the definition of discrete receptors. These models may be used in conjunction with rational drug design techniques to design novel PCP and sigma ligands of high selectivity and potency.
Mol Pharmacol 1988 Dec
PMID:Receptor site topographies for phencyclidine-like and sigma drugs: predictions from quantitative conformational, electrostatic potential, and radioreceptor analyses. 284 51

Phenycyclidine (PCP) produces many profound effects in the central nervous system. PCP has numerous behavioral and neurochemical effects such as inhibiting the uptake and facilitating the release of dopamine, serotonin, and norepinephrine. PCP also interacts with sigma, mu opioid, muscarinic, and nicotinic receptors. However, the psychotomimetic effects induced by PCP are believed to be mediated by specific PCP receptors, where PCP binds with greater potency than sigma compounds. Electrophysiological, behavioral, and neuro-chemical evidence strongly suggests that at least some of the many PCP actions result from antagonism of excitatory amino acid-induced responses via PCP receptors. The recent isolation and partial characterization of the alpha and beta endopsychosins and the identification of other endogenous ligands for the PCP and sigma receptors, is another promising area of research in the elucidation of the physiological role of an endogenous PCP and sigma system.
Mol Neurobiol 1987
PMID:Phencyclidine. Physiological actions, interactions with excitatory amino acids and endogenous ligands. 285 91

Biochemical and electrophysiological studies have provided evidence that a complex comprising the N-methyl-D-aspartate (NMDA)-type excitatory amino acid (EAA) receptor and the phencyclidine (PCP) recognition site exists in mammalian brain. This complex, which has been compared to that established for the inhibitory amino acid, gamma-aminobutyric acid, and the benzodiazepine anxiolytic, diazepam, is sensitive to the effects of the divalent cation Mg2+, which has suggested the presence of a third, ion channel component. Using a radioreceptor assay for the PCP receptor, L-glutamate (L-Glu) produced a concentration-dependent increase in the binding of [3H]thienyl cyclohexylpiperazine ([3H]TCP) in well washed membranes from rat forebrain. The EAA produced a maximal increase in specific binding of 400%, with an EC50 value of 340 nM. The ability of L-Glu to enhance [3H]TCP binding was 10-fold more potent in the presence of 30 microM Mg2+, which inhibits NMDA-evoked responses in intact tissue preparations and produces a 50% increase in [3H]TCP binding on its own. Analysis of saturation curves indicated that the effect of both L-Glu and Mg2+ could be attributed to an increase in receptor affinity as well as increases in the proportion of a high affinity state of the PCP-binding site. Assessment of the effect of a number of EAAs on basal [3H]TCP binding (well washed membranes in the absence of either L-Glu or Mg2+) showed that the EAA recognition site involved in the effects of L-Glu was the NMDA subtype. Further studies examined a series of compounds thought to interact with either the NMDA or PCP components of the receptor complex under four binding conditions: basal, +Mg2+; +L-Glu; and +Mg2+/L-Glu. These results showed that dissociative anesthetics, such as dexoxadrol and PCP, as well as the novel anticonvulsant MK-801, selectively interact with the high affinity state of the PCP receptor. NMDA antagonists, such as CPP, were also found to inhibit binding to the high affinity state of the PCP receptor, although not as potently as the dissociative anesthetics. Interestingly, the NMDA antagonists did not inhibit any of the binding to the low affinity state of the receptor. The sigma ligands (+/-)-SKF 10,047 and haloperidol recognized two components of [3H]TCP binding only in the presence of L-Glu. The results of the present study are consistent with the finding that agonists of the NMDA receptor induce a high affinity state of the PCP receptor.
Mol Pharmacol 1987 Dec
PMID:Interaction of L-glutamate and magnesium with phencyclidine recognition sites in rat brain: evidence for multiple affinity states of the phencyclidine/N-methyl-D-aspartate receptor complex. 289 25

The dynein arms that power ciliary motility are normally permanently attached by one end exclusively to subfiber A of each axonemal doublet (N) while the other (head) end transiently attaches to the subfiber B of the adjacent doublet (N + 1) to produce sliding of the doublets. In Tetrahymena axonemes, sliding of contiguous groups of doublets is induced by ATP suggesting that, in the absence of exogenous protease, there may be sets of potentially active and potentially inactive or refractory arms in a single axoneme. In the presence of a non-hydrolyzable analog of ATP, beta,gamma-methylene adenosine 5'-triphosphate (AMP-PCP), about half the doublets in an axonemal preparation retain all arms bound to subfiber A, but half the doublets show long regions where some arms are pulled away from subfiber A of doublet N and attached to subfiber B of doublet N + 1 by their head ends. In AMP-PCP-induced splaying, positional information regarding arm state is retained. Analysis reveals that throughout regions where B subfiber attachment is found, small groups of about four subfiber B attached arms alternate with groups of about four arms that remain attached to subfiber A. This unique pattern of attachment suggests that arms function co-operatively in groups of four. Further, the repetition of the pattern is reminiscent of metachronal activity seen at higher levels of biological organization. This suggests that in these regions we have instantaneously preserved groups of arms capable of attaching to and detaching from doublet N + 1 in rapid succession. This appearance could be used to delineate the potentially active sets of arm, primed for mechanochemical activity, within an axoneme.
J Mol Biol 1987 Oct 20
PMID:Dynein arm attachment probed with a non-hydrolyzable ATP analog. Structural evidence for patterns of activity. 296 33

The actions of the tertiary local anesthetic bupivacaine were studied on the nicotinic receptor-ionic channel complex (AChR) using electrophysiological and biochemical methods. Voltage clamp studies of the frog sartorius and cutaneous pectoris neuromuscular junction revealed a concentration-dependent depression of the decay time constant of the end-plate (tau EPC) and spontaneous miniature end-plate (tau MEPC) currents. The relationship of the reciprocal of either tau EPC or tau MEPC and bupivacaine concentration up to 100 microM was linear. Voltage dependence of EPC over the range +60 to -150 mV was reduced, whereas both EPC and MEPC decays were adequately described by a single exponential function at all concentrations tested. Peak MEPC and EPC amplitudes were also depressed in a concentration-dependent manner such that 100 microM bupivacaine reduced peak amplitude by about 50%. The current-voltage relationship remained linear under all conditions tested. Nerve-evoked responses were difficult to study at concentrations greater than 100 microM because of apparent blockade of nerve conduction. Extracellular recording of the MEPC afforded results similar to those obtained with EPCs. The tau MEPC could be reduced to less than 300 mu sec at a bupivacaine concentration of 400 microM. Fluctuation analysis showed that bupivacaine at concentrations of 10 and 25 microM did not change channel conductance but decreased single-channel lifetime to 76% and 39% of control values, respectively. Biochemical studies were performed on Torpedo californica membrane fragments using [3H]phencyclidine ([3H]PCP) and [3H]perhydrohistrionicotoxin ([3H]H12-HTX) as channel probes. Bupivacaine inhibited the binding of [3H]PCP and [3H]H12-HTX with inhibition constants (Ki) of 32 and 25 microM, respectively. The corresponding inhibition constants for bupivacaine methiodide were 1.8 and 3.2 microM. The preincubation of the membranes with carbamylcholine increased the affinity of bupivacaine for the ionic channel sites 5- to 8-fold and the affinity of bupivacaine methiodide 3- to 4-fold. Bupivacaine, however, had no affinity for the agonist recognition site as determined by [3H]ACh and [125I]alpha-bungarotoxin bindings. The electrophysiological and biochemical studies indicate that bupivacaine reacts primarily with the ionic channel of the nicotinic AChR. The results are consistent with a sequential model in which the drug interacts with the sites at the ionic channel of AChR in its open conformation, producing species with little or no conductance. From the present studies there is no evidence for an interaction of bupivacaine with the agonist binding site or closed states of AChR.
Mol Pharmacol 1984 Sep
PMID:Interactions of bupivacaine with ionic channels of the nicotinic receptor. Electrophysiological and biochemical studies. 609 Aug 84

In the presence of AMP-PCP (beta, gamma-methyleneadenosine 5'-triphosphate), a non-hydrolyzable analog of ATP, negative stain images of increased morphological detail indicate that the dynein arm, attached to ciliary doublet microtubules, is composed of subunits including a cape, an elongated body and a head. The arrangement of these subunits makes it possible to distinguish A from B subfiber binding sites on a single arm and to demonstrate that the head of an extended arm on subfiber A of one ciliary doublet is capable of binding to subfiber B of an adjacent doublet in a specific orientation, which supports a key step in a current model of the mechanochemical cycle by which the arm produces microtubule sliding in the ciliary axoneme.
J Mol Biol 1984 Mar 05
PMID:Dynein arm substructure and the orientation of arm-microtubule attachments. 623 Apr 60

[3H]Phencyclidine ( [3H]PCP) bound to crayfish abdominal muscle membranes at pH 7.4 with two affinities (Kd of 0.96 nM for 0.38 pmole/mg of protein, and 18.9 nM for 7.6 pmoles/mg of protein). Binding affinities increased at higher pH, suggesting that binding may be due mostly to the un-ionized form of [3H]PCP. This high-affinity [3H]PCP binding was sensitive to the actions of trypsin, protease, and dicyclohexylcarbodiimide, but insensitive to phospholipase A, concanavalin A,N-ethylmaleimide, and dithiothreitol. Calcium channel antagonists were most potent in inhibiting the high-affinity [3H]PCP binding with the following descending order of potencies: bepridil greater than nicardipine = diltiazem = verapamil greater than cinnarizine greater than (+)-D-600 greater than (-)-D-600 greater than 4-NO2-nifedipine greater than 2-NO2-nifedipine. The binding was also highly sensitive to several PCP analogues, antipsychotics, piperocaine , and tilorone, and moderately sensitive to d-tubocurarine, atropine, imipramine, nortryptyline , and tetracaine. Although verapamil and nifedipine inhibited the action potential of crayfish muscle, PCP did not and actually prolonged slightly the falling phase of the action potential. Although it is unlikely that the [3H]PCP binding protein in crayfish muscles is a Ca2+ channel, it is possible that it may be a K+ channel.
Mol Pharmacol 1984 May
PMID:Interactions of phencyclidine with crayfish muscle membranes. Sensitivity to calcium channel antagonists and other drugs. 632 63

Peptidases which are specific for proline residues have been described and include endopeptidases (post-proline cleaving enzyme and proline specific endopeptidase), N-terminal exopeptidases (post-proline dipeptidyl aminopeptidase, proline iminopeptidase, aminopeptidase P), C-terminal exopeptidases (prolylcarboxypeptidase, and carboxypeptidase P) and dipeptidases (prolyl dipeptidase and proline dipeptidase). The properties, distinguishing charcteristics, and possible significance of these proline specific endo- and exopeptidases are discussed. In addition, reference is made to a series of enzymes which can hydrolyze proline containing peptide bonds, but which are not specific for proline.
Mol Cell Biochem 1980 Apr 18
PMID:Proline specific endo- and exopeptidases. 699 12


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