Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “PIPERIDINES”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,459 records · Page 81Linked to original sources
PubMed1985

Effects of phencyclidine and analog drugs on acetylcholine receptor of cultured muscle cells.

Myotubes grown in culture provided a convenient experimental system for the study of the effects of phencyclidine (PCP) and analog drugs on both acetylcholine receptor (AChR) function and on its binding properties. The extent of PCP retention by these cells was studied on the same preparations. PCP, N-ethyl-l-phenylcyclohexylamine (PCE), PCP methiodide (PCPMeI), 1-[1-(3-aminophenyl)-cyclohexyl] piperidine (NH2PCP) and 1-[1-(2-thienyl)cyclohexyl] piperidine (TCP) were found to inhibit carbamylcholine (CbCh)-induced 22Na and 45Ca ion fluxes with 50% inhibition (I50) at 2-6 microM drug concentration. The I50 for CbCh-induced 42K+ efflux was 8-20 microM. Ketamine was less efficient with an I50 of 100 microM. Binding of [125I] alpha-bungarotoxin [( 125I]alpha-BGT) was not affected at drug concentrations that cause 100% inhibition of ion fluxes. Retention of [3H]PCP by the myotubes was a saturable process with half-maximal saturation at approximately 20 microM PCP. It was inhibited by PCP and several tertiary analogs, with and I50 of approximately 20 microM. PCPMeI was much less effective, with an I50 of 1 mM. PCPMeI was, however, as potent as PCP in its inhibition of the AChR function although the amount retained by the cells was 50-fold lower than that of PCP. These results are consistent with the theory that PCP and analog drugs affect AChR at a site other than the alpha-BGT binding site, possibly at the ionic channel of the nicotinic receptor.

Animals↗
PubMed1982

Response of Schaffer collateral-CA 1 pyramidal cell synapses of the hippocampus to analogues of acidic amino acids.

Analogues of the putative excitatory transmitters aspartic acid and glutamic acid were tested for antagonism against stimulus-evoked activation of Schaffer collateral-CA 1 pyramidal cell synapses in slices of rat hippocampus. Responses to the analogues, applied via the superfusing medium, were extracellularly recorded. The compounds examined included D- and L-alpha-aminodicarboxylic acids, diaminodicarboxylic acids, phosphonate analogues of acidic amino acids, D- and L-gamma-glutamyl glycine, and the cis- and trans-isomers of piperidine 2,3-, and 2,4-dicarboxylic acid. Many of these compounds are known to be potent and selective antagonists for excitatory amino acids and a few excitatory pathways. In this hippocampal pathway most of these analogues showed relatively low and similar potency. The most potent antagonist uncontaminated with agonist activity was D-alpha-aminosuberate, with an apparent antagonist dissociation constant (Kd) of 3 mM. Only 5 of the analogues, 3 of the piperidine dicarboxylates, kainic acid, and L-alpha-aminopimelic acid, reduced the amplitude of the extracellularly recorded field potentials more than 30% at 0.5 mM. However, all of the others reduced the potential by more than 30% at 5 mM. Most analogues also evoked extracellular responses which can be attributed to depolarization of the pyramidal neurons. Agonist activity was particularly strong among the most potent analogues. These results contrast with the responses documented by others for the N-methyl-D-aspartate receptor of the dorsal-ventral root excitatory pathway of the spinal cord in which the higher homologues tested here were the most potent antagonists, and the D-isomers were more potent than the L-isomers. It also contrasts with the response of the perforant path synapses to granule cells of the dentate gyrus in which the portion derived from the lateral entorhinal cortex is sensitive to L-2-amino-4-phosphonobutyric acid. Thus the Schaffer-CA 1 pyramidal cell synaptic field utilizes a novel excitatory transmitter receptor which interacts detectably but only weakly with a variety of acidic amino acids with potent specific inhibitory action for receptors elsewhere in the central nervous system.

Amino Acids, Dicarboxylic↗
PubMed1983

Antagonists of synaptic and amino acid excitation of neurones in the cat spinal cord.

In the spinal cord of the anaesthetized cat microelectrophoretically administered (+/-)-cis-2,3-piperidine dicarboxylate (2,3-PDA), (+/-)-cis-2,5-piperidine dicarboxylate (2,5-PDA), gamma-D-glutamylglycine (gamma DGG), beta-D-aspartyl-beta-alanine (beta DAA), (+/-)-2-amino-4-phosphonobutyrate (2-APB), (+/-)-2-amino-5-phosphonovalerate (2-APV) and (+/-)-2-amino-7-phosphonoheptanoate (2-APH) were assessed as antagonists of chemical excitation of dorsal horn interneurones and Renshaw cells by N-methyl-D-aspartate (NMDA), L-aspartate, quisqualate (QUIS), kainate and L-glutamate, and of monosynaptic and polysynaptic excitation by impulses in primary afferent fibres of muscle and cutaneous origin. Whereas polysynaptic excitation of interneurones was readily and reversibly depressed by 2-APV, 2-APH, beta DAA, gamma DGG and 2,3-PDA, all of which also reduced excitation by NMDA (and L-aspartate) more than that by QUIS (and L-glutamate), no selective antagonism of monosynaptic excitation could be demonstrated. In particular, 2,3-PDA, which depressed excitation by kainate to a greater extent than that by either QUIS or NMDA, appeared to have no effect on monosynaptic excitation. The results support the involvement of L-aspartate as the transmitter of some spinal excitatory interneurones, but none of the antagonists tested were considered suitable for assessing the role of L-glutamate as the transmitter of some spinal primary afferent fibres.

Amino Acids↗
PubMed1990

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.

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.

Adrenal Gland Neoplasms↗
PubMed1986

Anticholinesterase activity and structure activity relationships of a new series of hemicholinium-3 analogs.

Piperidine derivatives of hemicholinium-3 were synthesized and included the following spacing groups between the bis-cationic heads: trans,trans-bicyclohexyl, phenanthrene, naphthalene and biphenyl. Anticholinesterase activity was determined using rat striatal synaptosomal cholinesterase, bovine erythrocyte acetylcholinesterase and horse serum butyrylcholinesterase. Hemicholinium-3 has little anticholinesterase activity but when the choline moiety of hemicholinium-3 is replaced with selected heterocyclic amine ring systems active inhibitors can be obtained. Results in this communication identify several quaternary amines which are equipotent with physostigmine for inhibition of cholinesterase. Several tertiary amines were also found to be active. Optimal anticholinesterase activity of these piperidine derivatives appear to be related to the necessity of 14 A interatomic distance between the cationic heads as well as C = O substitution in the phenylethyl spacing moiety. Reduction of C = O to secondary alcohol or CH2 results in decreased activity. The anticholinesterase activity is not only related to internitrogen distance and C = O substitution but also structural planarity and positional isomerism of the quaternary cationic head.

Animals↗
PubMed1990

Anticonvulsant effects of antagonists of the N-methyl-D-aspartate receptor complex in a genetic model of epilepsy: the quaking mouse.

Tonic-clonic convulsions of mutant quaking mice were antagonized by the intracerebroventricular injection of N-methyl-D-aspartate receptor antagonists. The competitive antagonists, CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) and CGS 19755 (cis-4-(phosphonomethyl)-2-piperidine carboxylic acid), exerted a partial anticonvulsant action, with ED50S of 0.115 and 0.076 nmol, respectively. The non-competitive antagonists, TCP (1-(1-(2-thienyl)cyclohexyl)piperidine) and MK-801 [+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine), provided full protection, with ED50s of 4.49 and 2.67 nmol, respectively. The competitive antagonists elicited a marked ataxia whereas the non-competitive antagonists did not have side-effects. These results might reflect the involvement of glutamatergic neurotransmission in the convulsions of the quaking mutants.

Animals↗
PubMed1990

Excitatory amino acid-induced convulsions in neonatal rats mediated by distinct receptor subtypes.

We found that N-methyl-D-aspartate (NMDA) was a very potent, systematically active convulsant in the rat in the early period of postnatal development (7-11 days of age). Other receptor subtype-selective excitatory amino acid agonists were then examined for their convulsant effects following i.p. administration to neonatal rats. alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) was the most potent convulsant (ED50 0.6 mg/kg), followed by kainate (ED50 1.5 mg/kg), N-methyl-D-aspartate (NMDA) (ED50 3.1 mg/kg), then quisqualate (ED50 5.1 mg/kg). NMDA-induced convulsions were antagonized in a dose-related manner by prior administration of the NMDA antagonists cis-(+/- )-4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755), cis-(+/- )-4-(2H-tetrazol-5-yl)methyl-piperidine-2-carboxylic acid (LY233053), (+/- )3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), D,L-2-amino-5-phosphonovalerate (D,L-AP5) and MK801. NMDA antagonists did not protect against AMPA- or kainate-induced convulsions. 6,7-Dinitroquinoxaline-2,3-dione (DNQX) selectively prevented the effect of AMPA at doses which had no effect on NMDA or kainate convulsions. Quisqualate-induced convulsions were antagonized by NMDA antagonists or DNQX. The greater sensitivity of neonatal rats to systemically administered excitatory amino acid agonists appears useful for evaluating the selectivity of antagonists acting at ionotropic excitatory amino acid receptors in the central nervous system. Using neonatal rats three pharmacologically distinct excitatory amino acid receptor effects were demonstrated following administration of NMDA, AMPA or kainate.

Aging↗
PubMed1990

The effects of the phencyclidine analogs BTCP and TCP on nigrostriatal dopamine neuronal activity.

Extracellular single unit recording techniques were used to evaluate the effects of two phencyclidine (PCP) derivatives. N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP) and N-[1-(2-thiophenyl)cyclohexyl]piperidine (TCP) on the electrophysiological activity of antidromically identified nigrostriatal dopamine (DA) neurons in chloral hydrate-anesthetized rats. I.v. BTCP produced a dose-dependent decrease in the firing rate of identified nigrostriatal DA neurons whereas TCP elicited a dose-dependent biphasic effect which was characterized by an activation of cell firing at low doses followed by a reversal of the response with larger doses. A hemitransection of the brain anterior to the substantia nigra significantly reduced the inhibitory effect of BTCP while this surgical procedure did not affect the response to TCP. However, iontophoretic application of BTCP induced a current-dependent inhibition of the spontaneous activity of cells while local application of TCP had no effect on the firing rate of these cells. These data indicate that PCP analogs are able to interact with the nigrostriatal DAergic pathway through distinct and opposing mechanisms. The results are discussed in light of recent observations that BTCP is selective for the DA uptake site while TCP is selective for the high affinity PCP binding site.

Action Potentials↗
PubMed1991

Desipramine and the phencyclidine derivative BTCP differently inhibit [3H]TCP binding to high- and low-affinity sites.

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

Animals↗
PubMed1994

Comparative effects of selective kappa-opioid receptor agonists on dopamine levels in the dorsal caudate of freely moving rats.

Microdialysis was utilized to evaluate the effects of selective kappa-opioid receptor agonists on dopamine levels in the dorsal caudate of conscious rats. Subcutaneous administration of equivalent antinociceptive doses of spiradoline--(+/-)-(5 alpha, 7 alpha, 8 beta)-3, 4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl] benzeneacetamide--(U62066; 12 mg/kg), BRL 52656--(2S)-1-[(4- trifluoromethylphenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperidine--(2 mg/kg) and enadoline--(-)-(5 beta, 7 beta, 8 alpha)-N-methyl-N-[7-(1- pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzo[b]furan-4-acetamide-- (CI-977; 0.1 mg/kg) produced similar, statistically significant decreases in dorsal caudate dopamine levels; BRL 53001--(2S)-2- (dimethylaminomethyl)-1-[(5,6,7,8-tetrahydro-5-oxo-2-naphthyl)ace tyl] piperidine--(12 mg/kg) was, however, without effect. At a higher dose (36 mg/kgP, BRL 53001 also caused a significant reduction in dopamine levels. BRL 52974--4-(1-pyrrolidinylmethyl) 5-[(3,4-dichlorophenyl)acetyl]-4,5,6,7-tetrahydroimidazo[4,5-c] pyridine, a selective kappa-opioid receptor agonist with limited ability to cross the blood brain barrier or produce antinociceptive effects, had no effect on dopamine levels at 10 mg/kg s.c. Overall, these findings suggest that selective kappa-opioid receptor agonists decrease dopamine levels in the dorsal caudate of rats via a central locus of action. Furthermore, compared to other kappa-opioid receptor agonists, BRL 53001 appears to have a reduced propensity to decrease dopamine levels at equianalgesic doses.

Analgesics↗
PubMed1996

Effects of and interactions between antagonists for different sites on the NMDA receptor complex on hippocampal and striatal acetylcholine efflux in vivo.

Intraperitoneal administration of the non-competitive NMDA receptor antagonists (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801, 0.25 and 0.5 mg/kg) and 1-(1-phenylcyclohexyl)piperidine (PCP, 5 and 10 mg/kg) increased the extracellular concentration of acetylcholine in rat hippocampus but not striatum. In contrast, R-(+)-3-amino-1-hydroxypyrrolid-2-one (R(+)-HA-966, 30 and 60 mg/kg), an antagonist at the glycine modulatory site of the NMDA receptor, did not affect acetylcholine efflux in either region. (+/-)-3-[2-Carboxypiperazin-4-yl]-propyl-1-phosphonic acid ((+/-)CPP, 10 mg/kg) and cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS19755, 5 mg/kg), competitive antagonists at the glutamate agonist site of the NMDA receptor, marginally increased hippocampal acetylcholine efflux. Pretreatment with R(+)-HA-966 (60 mg/kg) or (+/-)CPP (10 mg/kg) attenuated the increase of hippocampal acetylcholine efflux by MK-801 (0.5 mg/kg). However, prior administration of CGS19755 (5 mg/kg) prolonged the MK-801-induced increase of hippocampal acetylcholine efflux. Results demonstrate differential effects on hippocampal and striatal acetylcholine efflux of antagonists at different sites on the NMDA receptor complex and are discussed in relation to previously described effects of these drugs on mesolimbic dopamine function.

Acetylcholine↗
PubMed1996

Autoradiographic study on the pharmacological characteristics of [3H]3-OH-PCP binding sites in rat brain.

The pharmacological characteristics and the regional distribution of [3H]3-OH-PCP (1-[1(3-hydroxyphenyl)-cyclohexyl]piperidine) binding were investigated in rat brain by quantitative autoradiography. Kinetic analysis of [3H]3-OH-PCP binding revealed fast and slow components, in the association and dissociation studies. The regional distribution of binding closely corresponded to those of binding sites labeled by [3H]N-[l-(2-thienyl)-cyclohexyl]3,4-piperidine (TCP) and [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne maleate (MK 801). High densities of [3H]3-OH-PCP binding sites were found in the stratum radiatum and orients of field CA1 in the hippocampus and in the outer layers of cerebral cortices. In contrast, low levels of binding were seen in the brain stem and the granular cell layer of the cerebellum. [3H]3-OH-PCP binding was strongly inhibited by MK 801 and 3-OH-PCP, while the potency of (+)-SKF 10047 in inhibiting [3H]3-OH-PCP binding was less in the cerebral cortex and hippocampus. The antagonists for the glutamate, glycine and polyamine recognition sites at the NMDA/PCP receptor complex displaced [3H]3-OH-PCP binding sites with a potency similar to that of [3H]MK 801. These findings suggest that the [3H]3-OH-PCP binding site is similar or identical to the PCP binding site labeled by [3H]TCP and [3H]MK 801.

Animals↗
PubMed1995

NE-100, a novel sigma ligand: effects on [3H]TCP binding to intact primary cultured neuronal cells.

N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100), a potent and highly selective sigma ligand, haloperidol, (+)pentazocine, 1-(cyclopropyl-methyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl) piperidine HBr (DuP 734) and 4-(2'-(4"-cyanophenyl)-2'-oxoethyl) 1-(cyclopropylmethyl)piperidine (XJ 448) inhibited carbachol-induced inositol 1,4,5-triphosphate (IP3) formation in a dose-dependent manner. The rank order of potency of the tested drugs for inhibition was: haloperidol > or = (+)pentazocine = NE-100 > DuP 734 = XJ 448. In addition, the effects of NE-100, DuP 734 and XJ 448 upon [3H]TCP binding were examined using primary cultured neuronal cells derived from the fetal rat telencephalon. These drugs inhibited [3H]TCP binding to intact cells. The ability of the test drugs to inhibit [3H]TCP binding to primary cultured neuronal cells was in the order: NE-100 > DuP 734 > XJ 448. These observations suggest that NE-100 indirectly modulates the N-methyl-D-aspartate (NMDA)/phencyclidine (PCP) receptor ion channel complex (NMDA receptor-ion channel), presumably through sigma-1 sites.

Animals↗
PubMed1982

Antagonists of excitatory amino acids and cyclic guanosine monophosphate in cerebellum.

The excitatory amino acid analogues kainate, quisqualate, domoic acid, 4-fluoroglutamate, homocysteic acid and N-methylaspartate as well as the tremor-inducing drugs harmaline and oxotremorine all induced significant elevations in cyclic guanosine monophosphate (cGMP) levels in the cerebellum in vivo. The putative antagonists of excitatory amino acids, 2-amino-5-phosphonovalerate (APV) and piperidine dicarboxylate (PDA) both blocked the actions of the tremorogens. Piperidine dicarboxylate also blocked the in vivo activity of all the amino acid analogues except homocysteic acid and N-methylaspartate. 2-Amino-5-phosphonovalerate (APV) was inactive against kainate, quisqualate and homocysteic acid. It therefore appears that PDA and APV are useful tools for the further study of the function of glutamate and asparatate receptors.

2-Amino-5-phosphonovalerate↗
PubMed1990

Wash-resistant inhibition of phencyclidine- and haloperidol-sensitive sigma receptor sites in guinea pig brain by putative affinity ligands: determination of selectivity.

Several putative affinity ligands, based on the structures of phencyclidine etoxadrol, 5-methyl-10,11-dihydro-5H-dibenzo[a,d] cycloheptene-5,10-imine (MK801) and 1,3-di-(2-methylphenyl)guanidine (DTG) were evaluated in vitro for their ability to produce a wash-resistant inhibition of phencyclidine and sigma receptor sites in homogenates of the brain of the guinea pig. All the phencyclidine-based ligands, including 1-[1-(3-isothiocyanatophenyl)cyclohexyl]piperidine (Metaphit) and (+/-)-N-(2-isothiocyanatoethyl) MK801 [(+/-)-MK801-NCS], produced a wash-resistant inhibition of binding sites for phencyclidine, labelled by [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) and sigma binding sites, labelled by [3H]DTG. The DTG-based ligands, 1-(4-isothiocyanato-2-methylphenyl)-3-(2-methylphenyl)guanidine (DIGIT) and 1-(4-[2-(2-isothiocyanatoethoxy)ethoxy]-2-methyl-phenyl)-3-(2- methylphenyl)guanidine (DIGIE), produced a wash-resistant inhibition of sigma sites, at concentrations as small as 1 microM and also inhibited binding sites for phencyclidine at larger concentrations (100 microM). Both 1-(3-isothiocyanatophenyl)-1-ethyl-4-(2-piperidyl)-1,3-dioxolane (ETOX-NCS) and 1-[1-(3-bromoacetyloxyphenyl)cyclohexyl]-1,2,3,6-tetrahydropyri din e (Bromoacetyl-PCP) were the most potent and selective inhibitors of the binding of [3H]TCP, while DIGIT was the most selective inhibitor of the binding of [3H]DTG. Future studies will examine the selectivity of these agents in vivo after intracerebroventricular administration.

Affinity Labels↗
PubMed1991

Quantitative characterization of multiple binding sites for phencyclidine and N-allylnormetazocine in membranes from rat and guinea pig brain.

Quantitative ligand binding studies have been used to characterize binding sites for N-allylnormetazocine ((+)SKF10,047) (SKF), 1-(1-phenylcyclohexyl) piperidine (PCP), N-[1-(2-thienyl)cyclohexyl]piperidine (TCP) and haloperidol in membranes from the brain of rat and guinea pig under conditions which permitted simultaneous analysis of the binding of both PCP and SKF. Using four labelled ligands (SKF, TCP, PCP and haloperidol), each displaced by the corresponding four unlabelled ligands, four classes of binding sites were observed in membranes from the brain of the rat, corresponding to sigma (sigma), two classes of PCP sites (PCP1, PCP2) and dopamine (D2) sites. The sigma site was suppressed by 50 nM haloperidol, while the PCP1 and PCP2 sites were not. These results were confirmed by studies employing a self- and cross-displacement design and dose-response surfaces for SKF and TCP, with and without blockade by haloperidol of the sigma site. Using mathematical modelling, employing the program LIGAND, it was possible to reject simpler models involving a common "PCP/sigma" site or a model involving only two classes of sites (sigma and PCP). Similar methods were used to identify two classes of sigma binding sites and two classes of PCP binding sites, in membranes prepared from the brain of the guinea pig. The relative potencies of 18 ligands for displacement of (+)[3H]SKF10,047 and [3H]TCP were compared: there were significant qualitative and quantitative differences in the "sigma" binding sites in the brain of rat and guinea pig, while the PCP binding sites were very similar in the two species.

Animals↗
PubMed1981

Discriminative stimulus properties of phencyclidine and five analogues in the squirrel monkey.

Squirrel monkeys were trained to discriminate 0.16 mg/kg of 1-(1-phenylcyclohexyl) piperidine (PCP) from saline in a two-lever drug discrimination task on a fixed-ratio 32 schedule of food presentation. Intramuscular injections were given 5 min pre-session in a double alternation pattern. After reliable discriminative control of lever choice was established, dose-response determinations for generalization to the training dose of PCP was made with several doses of PCP, N-ethyl-1-phenylcyclohexylamine (PCE), 1-[1-(2-thienyl)cyclohexyl] piperidine (TCP), 1-(1-phenylcyclohexyl) morpholine (PCM), 1-(1-phenylcyclohexyl) pyrrolidine (PHP), and ketamine. All drugs produced dose-dependent PCP-appropriate responding. For each analogue, a dose was found which produced stimulus control of responding comparable to that of the PCP training dose. ED50 values were determined for each drug for percent drug-lever appropriate responding and for suppression of operant responding during test sessions. The relative potency for producing drug-lever appropriate responding was: TCP greater than PCP = PCE greater than PHP greater than PCM greater than ketamine. The relative potency for suppression of operant responding was: PCP = TCP greater than PHP greater than PCE greater than PCM greater than ketamine. In all cases, the dose necessary to suppress operant responding to fifty percent of vehicle rates was three to five times larger than the ED50 dose for drug-lever appropriate responding. The results of this study indicate marked similarities in the behavioral effects of these six arylcyclohexylamines.

Animals↗
PubMed1986

Acylating phencyclidines irreversibly enhance brain calcium antagonist binding.

Phencyclidine was previously shown to allosterically increase the apparent affinity of the dihydropyridine ( [3H]nitrendipine) calcium antagonist binding site in a lysed synaptosomal membrane preparation of rat forebrain. Treatment of a similar preparation of mouse forebrain with 4-isothiocyanato-1-(1-phenylcyclohexyl) piperidine (FOURPHIT), an acylating phencyclidine derivative, resulted in a concentration dependent (0.1-10 microM), irreversible, increase in the apparent affinity of [3H]nitrendipine in contrast to the effects of phencyclidine which were reversible. The FOURPHIT isomer, 1-[1-(3-isothiocyanatophenyl) cyclohexyl] piperidine (METAPHIT), (10 microM) also irreversibly increased the apparent affinity of [3H]nitrendipine, but was much less efficacious than FOURPHIT. Phencyclidine blocked the irreversible increase in the apparent affinity of [3H]nitrendipine produced by FOURPHIT. The interactions of multivalent cations and the calcium antagonist diltiazem with the [3H]nitrendipine binding site were altered following treatment of membranes with FOURPHIT. These studies suggest that FOURPHIT irreversibly interacts with the same sites as PCP, and thus may be a useful tool with which to further probe both the behavioral and biochemical interactions between phencyclidine and the dihydropyridine calcium antagonist binding site.

Animals↗