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)

Certain benzeneacetamides [(-)- and (+)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide] were recently reported to be potent sigma receptor ligands. In order to determine whether efficacy for the sigma receptor could be improved, a series of compounds related to the benzeneacetamides, N-substituted cis-2-(1-pyrrolidinyl)-N-methylcyclohexylamines, were synthesized and their structure-activity requirements were determined. The compounds were synthesized by starting with the previously reported (+/-)-, 1S,2R-(+)-, and 1R,2S-(-)-cis-2-(1-pyrrolidinyl)-N-methylcyclohexylamines. Analysis of sigma ([3H](+)-3-PPP), kappa ([3H]bremazocine and [3H]U69,593), dopamine-d2 ([3H](-)-sulpiride), and phencyclidine (PCP) ([3H]TCP) receptor binding in guinea pig brain revealed a number of highly potent and selective sigma receptor ligands. Notably, 1S,2R-cis-(-)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-(2-naphthyl) acetamide [(-)-29] (Ki = 8.66 +/- 0.35 nM), (+/-)-cis-2-amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide [(+/-)-17] (Ki = 11 +/- 3 nM), 1S,2R-(-)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl ) cyclohexylamine [(-)-44] (Ki = 1.3 +/- 0.3 nM), and 1R,2S-(+)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl ) cyclohexylamine. [(+)-44] (Ki = 6 +/- 3 nM) exhibited very high affinity at sigma receptors, by displacement of [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [( 3H]-(+)-3-PPP). These compounds showed insignificant affinity for kappa, dopamine, or PCP receptors, making them valuable tools for the study of sigma receptors. Furthermore, these compounds also exhibited enantioselectivity ranging from 5-fold for (+)- and (-)-44 to 160-fold for (+)- and (-)-29. Several other compounds showed equivalent selectivity but displayed lower sigma receptor affinity.
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PMID:Synthesis and evaluation of N-substituted cis-N-methyl-2-(1-pyrrolidinyl)cyclohexylamines as high affinity sigma receptor ligands. Identification of a new class of highly potent and selective sigma receptor probes. 217 38

Two highly selective radiolabeled probes for sigma receptors were found to bind with high affinity and capacity to membranes from undifferentiated PC12 cells. [3H]1,3-di-o-tolylguanidine [( 3H]DTG) bound with Kd = 23.7 +/- 4.6 nM and Bmax = 2025 +/- 660 fmol/mg protein. The Kd and Bmax for [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H](+)-3-PPP) were 86.3 +/- 21.6 nM and 1539 +/- 242 fmol/mg protein, respectively. These binding parameters were comparable to those observed in guinea pig brain, although the Kd for [3H](+)-3-PPP was 3-fold higher in the PC12 membranes. Both the PC12 and guinea pig brain sites exhibited high affinity for haloperidol, moderate affinity for phencyclidine (PCP), and negligible affinity for MK-801, apomorphine, and (-)-sulpiride. These data suggest a relationship of the PC12 site to sigma receptors. However, all (+)-opiates [+)-benzomorphans and (+)-morphinans) tested bound with markedly lower affinity to the PC12 site compared to guinea pig brain. These include (+)-N-allylnormetazocine [+)-SKF 10,047), (+)-pentazocine, and dextrallorphan. In fact, PC12 sites exhibited preference for (-)-benzomorphans, the reverse stereoselectivity of guinea pig brain sites. Binding of [3H]N-[1-(2-thienyl)cyclohexyl]piperidine [( 3H]TCP) could not be detected, demonstrating absence of PCP receptors on this cell line. Differentiation of cells by treatment with nerve growth factor had no effect on sigma binding parameters. Membranes from guinea pig brain and PC12 cells were photoaffinity-labeled using [3H]azido-di-o-tolylguanidine. In guinea pig brain, a polypeptide of 25 kDa was specifically labeled. However, label was incorporated into polypeptides of 18 kDa and 21 kDa in membranes from PC12 cells. In view of the otherwise similar binding characteristics, the marked differences in affinity for (+)-benzomorphans and molecular weight suggest that PC12 cells contain a molecular form of sigma receptor distinct from that predominant in guinea pig brain. This raises the possibility of multiple sigma receptor types.
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PMID:A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain. 217 17

1. CI-977 is a new, nonpeptide kappa-opioid compound that has been synthesized and its pharmacological properties determined in a series of in vitro and in vivo rodent models. 2. In a radioligand binding studies, with guinea-pig forebrain homogenates, CI-977 bound with high affinity to [3H]-U69593-labelled kappa-sites (Ki = 0.11 nM) but with low affinity to [3H]-[D-Ala2, MePhe4, Gly-ol5] enkephalin (DAMGO) labelled mu-sites (Ki = 99 nM) and [3H]-[D-Pen2.5]enkephalin (DPDPE) labelled delta-sites (Ki = 1.04 microM). CI-977 also bound with negligible affinity to [3H]-(+)-3-(1-propyl-3-piperi-dinyl)phenol (3-PPP) labelled sigma-sites (Ki = 1.9 microM) and [3H]-1-(1-[2-thienyl]cyclohexyl)piperidine (TCP) labelled PCP sites (Ki greater than 10 microM). 3. CI-977 produced a potent inhibition of the electrically-evoked contractions of the guinea-pig ileum and rabbit vas deferens with IC50 values of 0.087 nM and 3.3 nM, respectively. The pKB values for the opioid antagonists naloxone (7.6) and norbinaltorphimine (10.5) supported the kappa nature of the CI-977-mediated effects in the smooth muscle assays. 4. CI-977 was a potent antinociceptive agent against a mechanical noxious stimulus in rats following intravenous, intramuscular, subcutaneous and oral administration. CI-977 was also effective against mechanical and chemical noxious stimuli in the mouse but ineffective against a thermal stimulus. The antinociceptive effects produced by CI-977 were completely reversed by naloxone (1 mg kg-1, s.c.). 5. At doses close to those required to produce antinociception, CI-977 also caused a naloxone-reversible diuresis and inhibition of locomotor activity.6. The in vitro and in vivo pharmacological profile of CI-977 demonstrates that it is a potent and selective agonist at the Kappa-opioid receptor.
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PMID:CI-977, a novel and selective agonist for the kappa-opioid receptor. 217 14

We studied the effects of several prototypic sigma site ligands on the binding of [3H]dextromethorphan ([3H]DM) to guinea pig brain. Haloperidol, 3-(-3-Hydroxyphenyl)-N-(1-propyl)piperidine [+)-3-PPP) and (+)-N-allyl-N-normetazocine [+)-NANM or (+)-SKF10,047), which are potent sigma site ligands, showed high affinity for [3H]DM binding sites. The rank order of potency of sigma ligands, as indicated by the Ki values for the high-affinity sites is: haloperidol greater than (+)-pentazocine greater than (+)-cyclazocine greater than (+)-SKF10,047 greater than (-)-butaclamol much greater than (+)-butaclamol greater than (-)-SKF10,047. This rank order of potency is similar to that for the sites labeled with [3H](+)-3-PPP and [3H](+)-SKF10,047. The (+)-isomers of several benzomorphans displayed higher affinity than the (-)-isomers. (-)-Butaclamol competed against [3H]DM binding more effectively than the (+)-isomer, displaying the same stereospecificity shown for sigma sites. The findings reported here demonstrate that there are previously unrecognized similarities between DM and sigma sites. It is evident that further exploration of the DM, sigma and phencyclidine (PCP) sites will be necessary to establish the physiological role and therapeutic potential of these sites.
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PMID:The effect of prototypic sigma ligands on the binding of [3H]dextromethorphan to guinea pig brain. 253 77

Pretreatment of guinea pig brain membranes with 1-[1-(3-isothiocyanatophenyl)cyclohexyl]piperidine (Metaphit) caused irreversible and differential inhibition of ligand binding to sigma (sigma) receptors. The concentration of Metaphit required to produce 50% inhibition of binding of [3H]1,3-di-o-tolylguanidine ([3H]DTG), [3H](+)-3-(3-hydroxy-phenyl)-N-(1-propyl)piperidine ([3H](+)-3-PPP), and [3H](+)-N-allylnormetazocine ([3H](+)-SKF 10,047) to sigma receptors was 2, 10 and 50 microM, respectively. This compares to a value of 10 microM for inhibition of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine [( 3H]TCP) binding to phencyclidine (PCP) receptors. While Metaphit was an irreversible, non-competitive inhibitor at PCP receptors, this compound produced irreversible, competitive inhibition at sigma receptors.
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PMID:Acylation of sigma receptors by Metaphit, an isothiocyanate derivative of phencyclidine. 254 47

The synthesis and in vitro sigma receptor activity of the two diastereomers of U50,488 [(+/-)-2], namely, (1R,2S)-(+)- cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacet ami de [(+)-1] and (1S,2R)-(-)-cis-3,4-dichloro- N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-1], are described. (+)-1 and (-)-1 were synthesized from (+/-)-trans-N-methyl-2-aminocyclohexanol [(+/-)-3]. Pyridinium chlorochromate (PCC) oxidation of the N-t-Boc-protected derivative of (+/-)-3 afforded (+/-)-2-[N- [(tert-butyloxy)carbonyl]-N-methylamino]cyclohexanone [(+/-)-5]. The sequence of enamine formation with pyrrolidine, catalytic reduction, N-deprotection, and optical resolution afforded (1R,2S)-(-)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(-)-10] and (1S,2R)-(+)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(+)-10]. The optical purity (greater than 99.5%) of (-)-10 and (+)-10 was determined by HPLC analysis of the diastereomeric ureas formed by reaction with optically pure (R)-alpha-methylbenzyl isocyanate. The absolute configuration of (-)-10 and (+)-10 was determined by single-crystal X-ray diffractometry of the bis-(R)-mandelate salt. Condensation of optically pure (-)-10 and (+)-10 with 3,4-dichlorophenylacetic acid furnished (+)-1 and (-)-1, respectively. Compounds (+)-1, (-)-1, (-)-2, and (+)-2 were compared for their binding affinities at kappa opioid, sigma, D2-dopamine, and phencyclidine (PCP) receptors in competitive binding assays using [3H]bremazocine ([3H]BREM) or [3H]U69,593, [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [[3H]-(+)-3-PPP], or [3H]-1,3-di(o-tolyl)guanidine ([3H]DTG), [3H]-(-)-sulpiride [[3H]-(-)SULP], and [3H]-1- [1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP), respectively. In the systems examined, (-)-2 exhibited the highest affinity for kappa receptors, with a Ki of 44 +/- 8 nM. However, (-)-2 also showed moderate affinity for sigma receptors, with a Ki of 594 +/- 3 nM [[3H]-(+)-3-PPP]. The (1R,2R)-(+)-enantiomer, (+)-2, had low affinity for both kappa and sigma receptors, exhibiting Ki values of 1298 +/- 49 nM at kappa ([3H]BREM) and 1270 +/- 168 nM at sigma [[3H]-(+)-3-PPP]. In contrast, the chiral cis compounds (+)-1 and (-)-1 showed high affinity for sigma receptors and negligible affinity for kappa opioid receptors in the [3H]BREM assay. Compound (-)-1 exhibited a Ki of 81 +/- 13 nM at sigma receptors [[3H]-(+)-3-PPP] and 250 +/- 8 nM ([3H]DTG).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alterations in the stereochemistry of the kappa-selective opioid agonist U50,488 result in high-affinity sigma ligands. 254 74

These experiments were designed to compare phencyclidine (PCP) and sigma (sigma) receptor binding sites in the rat spinal cord by using receptor binding and autoradiographic techniques. Binding sites for 3H-TCP (3H-1-[1-(2-thienyl)cyclohexy]piperidine), a PCP receptor agonist, and (+)3H-3-PPP (3H-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine), a sigma receptor agonist, in the rat spinal cord were shown to represent two populations of recognition sites. Inhibition studies revealed that ligands with high affinity for the PCP receptor (MK-801 and PCP) were potent competitors at 3H-TCP binding sites whereas the putative sigma receptor ligands (+/-)pentazocine and haloperidol were potent competitors at (+)3H-3-PPP binding sites. The autoradiographic distribution of 3H-TCP and (+)3H-3-PPP binding sites in adjacent sections of rat spinal cord demonstrated the occurrence of two distinct populations of binding sites. 3H-TCP binding sites were localized primarily in laminae I and II in cervical and thoracic spinal segments. Binding sites in lamina I decreased in density along a rostral to caudal gradient in the spinal cord. The highest density of (+)3H-3-PPP binding sites was found in the ventral horn (lamina VIII and IX) and over perikarya in dorsal root ganglia. Significantly elevated densities of (+)3H-3-PPP binding sites were also found in lamina X within thoracic and lumbar segments and in the intermediolateral cell column. The results of the present study show that PCP and sigma receptor binding sites are differentially localized in the rat spinal cord and suggest that separate binding sites exist for PCP and sigma agonists.
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PMID:Phencyclidine and sigma receptors in rat spinal cord: binding characterization and quantitative autoradiography. 254 51

Whole-cell voltage-clamp recording techniques were used to investigate the blockade of voltage-dependent K+ channels by phencyclidine (PCP) in cultured rat hippocampal neurons. All recordings were carried out in the presence of tetrodotoxin (1-2 microM) to eliminate Na+ currents. Step depolarization from a holding potential of -40 mV activated a slowly rising, minimally inactivating K+ current (IK). PCP (0.5-1000 microM) caused a reduction in the maximum conductance of IK [IC50(+30 mV), 22 microM] without altering its voltage dependency. The PCP block of IK diminished at depolarized potentials. Analysis according to the scheme of Woodhull (1973) suggested that block occurs via binding to an acceptor site (presumably within the channel pore) that senses 40-50% of the transmembrane electrostatic field. PCP had no effect on the kinetic properties of IK and the block failed to show use dependency, suggesting that PCP may bind to the IK channel via a hydrophobic mechanism not requiring open channels. For comparison, we also investigated the effect of PCP on the transient K+ current, IA, activated by step depolarization following a 200 msec prepulse to -90 mV (20 mM tetraethylammonium was present in the bathing solution to reduce IK). In contrast to the potent blocking action of PCP on IK, the drug only affected IA at high concentrations [IC50(+30 mV), 224 microM]. At concentrations causing substantial block (300-500 microM), PCP produced an acceleration in the IA inactivation rate, and, for brief (5-6 msec) depolarizing steps, the suppression of IA was use dependent. These observations suggest that PCP block of IA requires open channels. PCP reduced inward current responses induced by the excitatory amino acid agonist N-methyl-D-aspartate (NMDA) at substantially lower concentrations than those required for its effects on K+ channels [IC50(-60 mV), 0.45 microM]. The PCP-like dioxadrol stereoisomer dexoxadrol (10 microM) blocked NMDA-evoked inward current responses, while its behaviorally inactive enantiomer levoxadrol did not. Dexoxadrol and levoxadrol also blocked IK in a stereoselective fashion (IC50's, 73 and 260 microM, respectively), whereas the sigma ligands (+)- and (-)-SKF 10,047 and (+)-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine [(+)-3-PPP] had little effect on the current (IC50's, greater than 300-500 microM). We conclude that PCP causes a selective, voltage-dependent block of IK in hippocampal neurons via a PCP- and not a sigma-type acceptor site.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Interaction of phencyclidine with voltage-dependent potassium channels in cultured rat hippocampal neurons: comparison with block of the NMDA receptor-ionophore complex. 255 61

[11C]Carfentanil is a potent opioid agonist currently in use as a specific PET (position emission tomography) scan radioligand for brain mu opioid receptors. In order to investigate the receptor interactions of carfentanil in detail [3H]carfentanil was used as a radioligand for labelling receptors in rat and human brain tissue homogenates. [3H]Carfentanil was found to bind saturably and with high affinity (KD = 0.08 +/- 0.01 nM) to membranes prepared from human cortical (Bmax = 42 +/- 3 fmol/mg) and thalamic (Bmax = 84 +/- 3 fmol/mg) tissues and rat cortex (Bmax = 82 +/- 4 fmol/mg) and diencephalon (Bmax = 105 +/- 5 fmol/mg). Association (1.23 +/- 0.19 X 10(10) Mol-1 X min-1 and dissociation rate (0.19 +/- 0.03 min-1) constants were determined in human cortical tissues; results from studies in rat cortical, and rat diencephalon tissue homogenates produced similar kinetic rate constants. Competition studies with a variety of drugs indicated that [3H]carfentanil interacts primarily with mu opioid receptors in the four tissues studied; the affinities of a series of non-radioactive opioid ligands were essentially identical in the four tissues (correlation coefficients = 0.88-0.93). Naloxone, morphine, DAGO [( D-Ala2-MePhe4-Gly-ol5]enkephalin), DADL [( D-Ala2-D-Leu5]enkephalin) and EKC (ehtylketazocine) potently displaced specific [3H]carfentanil binding with nM potency while the kappa agonist U-69593, the sigma agonists (+)-SKF 10047, (+)-3-PPP [3-hydroxyphenyl)-N-propylpiperidine) and haloperidol and PCP (phencyclidine) were less potent displacing agents. The higher affinities of DAGO and morphine versus DADL for the [3H]carfentanil binding sites indicates that delta opioid receptors are not being labelled.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mu opiate receptors are selectively labelled by [3H]carfentanil in human and rat brain. 255 84

Tritium-labeled (+)-pentazocine ([3H]-1b) of specific activity 26.6 Ci/mmol was synthesized in 3 steps starting with (+)-normetazocine (2) of defined optical purity. [3H]-1b has been characterized as a highly selective ligand for labeling of sigma receptors. Competition data revealed that [3H]-1b could be displaced from guinea pig brain membrane preparations with a number of commonly used sigma receptor ligands. [3H]-1b exhibited saturable, enantioselective binding with a Kd of 5.13 +/- 0.97 nM and a Bmax of 1146 +/- 122 fmol/mg protein. Phencyclidine (PCP) displaced [3H]-1b with low affinity while MK-801 was inactive, thus indicating insignificant activity at the PCP-binding site; apomorphine failed to displace [3H]-1b indicating lack of dopamine receptor cross-reactivity. Since the affinity of [3H]-1b is about 6 times that of the two commonly employed sigma ligands ((+)-3-[3H]PPP and [3H]DTG) and since it is more selective for sigma receptors than the benzomorphan [3H]SKF-10,047, it represents the first example of a highly selective benzomorphan based sigma receptor ligand. [3H]-1b should prove useful for further study of the structure and function of sigma receptors.
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PMID:Synthesis and evaluation of optically pure [3H]-(+)-pentazocine, a highly potent and selective radioligand for sigma receptors. 256 52


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