piperidines and dioxadrol

In the mid 1960s the (dioxolan-4-yl)piperidine derivatives dexoxadrol ((S,S)-1a) and etoxadrol ((S,S,S)-2a) were synthesized. Their pharmacological potential as analgesics, anesthetics and local anesthetics was evaluated in animal models and later on in clinical trials with patients. However, severe side effects including psychotomimetic effects, unpleasant dreams and aberrations stopped the clinical evaluation of dexoxadrol and etoxadrol. Both dioxolane derivatives represent NMDA receptor antagonists, which possess high affinity to the phencyclidine binding site within the NMDA receptor associated ion channel. In this review relationships between the structure of acetalic dexoxadrol analogues and homologues and their affinity toward the phencyclidine binding site of the NMDA receptor are summarized. In particular, high affinity is attained with compounds bearing two phenyl residues or one phenyl residue and an alkyl residue with two or three carbon atoms at the acetalic center. At least one oxygen atom of the oxygen heterocycle is necessary. Instead of the entire piperidine ring aminoalkyl substructures are sufficient for strong receptor interactions. Compounds with a primary amino moiety generally display the highest receptor affinity, whereas tertiary amines possess low affinity. Enlargement of the 1,3-dioxolane ring to a 1,3-dioxane ring or elongation of the oxygen heterocycle / amino group distance results in compounds with considerable NMDA receptor affinity.

Topics: Animals; Dioxolanes; Excitatory Amino Acid Antagonists; Humans; Models, Molecular; Oxygen; Piperidines; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship

A series of dioxadrol analogues with fluorine substituents in position 4 of the piperidine ring has been synthesized and pharmacologically evaluated. The key step in the synthesis was the fluorination of diastereomeric piperidones 6a and 6c as well as diastereomeric alcohols 9a and 9c with DAST. The reaction of the alcohols 9a and 9c took place with inversion of configuration. After removal of the Cbz-protective group, the NMDA receptor affinities of the resulting secondary amines 8a, 8c, 12b, and 12d were investigated in receptor binding studies. It was shown that the like-configuration of the ring junction was crucial for high NMDA receptor affinity. An axially oriented fluorine atom in position 4 led to 2-(2,2-diphenyl-1,3-dioxolan-4-yl)-4-fluoropiperidine (12d, WMS-2517) with a K(i)-value of 27nM. The NMDA receptor affinity of 8c (WMS-2513) with an additional fluorine atom in equatorial 4-position was slightly reduced (K(i)=81 nM). Both fluorinated dioxadrol derivatives 8c and 12d showed high selectivity against sigma(1) and sigma(2) receptors as well as the polyamine binding site of NR2B receptors.

Topics: Alcohols; Amines; Analgesics; Binding Sites; Dioxolanes; Halogenation; Humans; Piperidines; Piperidones; Protein Binding; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship

A series of chiral non-racemic dexoxadrol analogues with various substituents in position 4 of the piperidine ring was synthesized and pharmacologically evaluated. Only the enantiomers having (S)-configuration at the 2-position of the piperidine ring and 4-position of the dioxolane ring were considered. Key steps in the synthesis were an imino-Diels-Alder reaction of enantiomerically pure imine (S)-13, which had been obtained from d-mannitol, with Danishefsky's Diene 14 and the replacement of the p-methoxybenzyl protective group with a Cbz-group. It was shown that (S,S)-configuration of the ring junction (position 2 of the piperidine ring and position 4 of the dioxolane ring) and axial orientation of the C-4-substituent ((4S)-configuration) are crucial for high NMDA receptor affinity. 2-(2,2-Diphenyl-1,3-dioxolan-4-yl)piperidines with a hydroxy moiety ((S,S,S)-5, K(i)=28nM), a fluorine atom ((S,S,S)-6, WMS-2539, K(i)=7nM) and two fluorine atoms ((S,S)-7, K(i)=48nM) in position 4 represent the most potent NMDA antagonists with high selectivity against σ(1) and σ(2) receptors and the polyamine binding site of the NMDA receptor. The NMDA receptor affinities of the new ligands were correlated with their electrostatic potentials, calculated gas phase proton affinities (negative enthalpies of deprotonation) and dipole moments. According to these calculations decreasing proton affinity and increasing dipole moment are correlated with decreasing NMDA receptor affinity.

Topics: Animals; Binding Sites; Brain; Dioxolanes; Models, Theoretical; Piperidines; Receptors, N-Methyl-D-Aspartate; Static Electricity; Stereoisomerism; Structure-Activity Relationship; Swine

The synthesis and NMDA receptor affinity of ring and side-chain homologues of etoxadrol and dexoxadrol are described. For the regioselective synthesis of etoxadrol homologues, the regioisomeric 4-azidobutanediols (+/-)-9 and (+/-)-14 were employed. A synthesis of the enantiomerically pure azidobutanediols (S)-, (R)-9 and (S)-, (R)-14 was developed and the homochiral building blocks were used for the synthesis of enantiomerically pure etoxadrol and dexoxadrol homologues. The affinity of the racemic and enantiomerically pure primary amines toward the phencyclidine binding site of the NMDA receptor was investigated in receptor binding studies with tritium labeled [3H]-(+)-MK-801 as radioligand. Benzaldehyde derivatives (+/-)-12a, (+/-)-13a, and (+/-)-16a bearing a proton at the acetalic position do not interact significantly with the NMDA receptor. An enantioselective NMDA receptor binding was observed for the trans-configured 2-(2-ethyl-2-phenyl-1,3-dioxolan-4-yl)ethanamine 13b, the (2-ethyl-2-phenyl-1,3-dioxan-4-yl)methanamine 16b, and the (2,2-diphenyl-1,3-dioxan-4-yl)methanamine 16c. The NMDA receptor affinity of these compounds resides almost exclusively in the (S)-configured enantiomers (2S,4S)-13b, (2S,4S)-16b, and (4S)-16c. The lowest Ki-value in this series was found for the (2S,4S)-configured 1,3-dioxolane (2S,4S)-13b (Ki = 69 nM), which is in the range of the Ki-value of the lead compounds etoxadrol and dexoxadrol, indicating that the 2-aminoethyl and the piperidin-2-yl substituents lead to similar NMDA receptor interactions.

Topics: Animals; Dioxolanes; Guinea Pigs; Molecular Structure; Piperidines; Receptors, N-Methyl-D-Aspartate; Stereoisomerism; Structure-Activity Relationship

The regioselectivity during transacetalization of benzophenone dimethyl acetal (4) with butane-1, 2, 4-triol (5) is controlled by the reaction conditions. Thermo-dynamic control leads predominantly to the 1, 3-dioxolane 6 whereas kinetic control favors the six-membered acetal 7. The amines 2a-e and 3a-e are synthesized from the alcohols 6 and 7 and are investigated in receptor binding studies with radioligands for their affinity to the phencyclidine binding site of the NMDA-receptor. In both series the primary amines 2a and 3a show the highest NMDA-receptor affinity (2a: Ki=3.38 microM; 3a: Ki=1.45 microM). The NMDA receptor slightly prefers the 1, 3-dioxane derivatives 3a and 3b compared to 2a and 2b (factor 2-3). Low interactions of the amines 3a and 3b with various receptor and reuptake systems indicate selectivity for the NMDA receptor. Surprisingly, the piperidine derivative 2e binds with high affinity at sigma1-receptors and, therefore, represents a novel lead compound for high affinity sigma1-receptor ligands.

Topics: Analgesics; Animals; Dioxolanes; Guinea Pigs; Piperidines; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship; Swine

The ability of non-competitive NMDA antagonists and other selected compounds to inhibit [3H]MK-801 binding to the NMDA receptor in brain membranes was evaluated in female, dark Agouti rats. In homologous competition binding studies the average apparent affinity (KD) of [3H]MK-801 for its binding site was 5.5 nM and the binding site density (Bmax) was 1.83 pmol/mg protein. Inhibition of [3H]MK-801 binding by non-competitive NMDA antagonists was best described with a one-site competition model and the average Hill coefficients were -1. A series of eight non-competitive NMDA antagonists inhibited [3H]MK-801 binding with the following rank order of affinity (K(i), nM): MK-801 (5.5) > dexoxadrol (21.5) > or = TCP (24.2) > phencyclidine (100.8) > (+)-SKF 10,047 (357.7) > dextrorphan (405.2) > ketamine (922.2) > dextromethorphan (2913). These inhibition binding constants determined in dark Agouti rat brain membranes were significantly correlated (P = 0.0002; r2 = 0.95) with previously reported values determined in Sprague-Dawley rats [Wong et al., 1988, J. Neurochem. 50, 274-281]. Despite significant differences in metabolic capability between these strains, the central nervous system NMDA receptor ion channel shares similar characteristics.

Topics: Animals; Binding, Competitive; Brain; Dextromethorphan; Dioxolanes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Ketamine; N-Methylaspartate; Phenazocine; Phencyclidine; Piperidines; Rats; Rats, Mutant Strains; Receptors, N-Methyl-D-Aspartate; Scintillation Counting; Tritium

Since the three-dimensional structure of the NMDA receptor has not been determined experimentally, indirect computer-assisted molecular modeling techniques appear to be of great usefulness in the characterization of the common pharmacophore of all NMDA receptor noncompetitive antagonists, despite their structural differences. Indeed, the conformational analysis of three different chemical families (MK801, PCP, dexoxadrol and their analogues), has allowed us to visualize the different conformations and configurations of each molecule. Superimposition with configurations 1 and 2 of the MK801 molecule has allowed us to propose active conformations and thereafter a geometrical characterization of the pharmacophore, especially the determination of the orientation of the nitrogen lone pair (NLP) related to the phenyl. On the other hand, electrostatic studies, combined with geometrical features, have allowed us to schematize the interaction mode of an active conformation to the binding site. Finally, studies of the molecular lipophilic potential (MLP) have provided us information on the position of lipophilic and hydrophilic zones of the pharmacophore.

Topics: Binding Sites; Dioxolanes; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Ketamine; Lipids; Models, Molecular; Molecular Structure; N-Methylaspartate; Nitrogen; Phencyclidine; Piperidines; Quinolines; Receptors, N-Methyl-D-Aspartate; Static Electricity

The dizocilpine-like discriminative stimulus effects of a variety of channel blocking (uncompetitive) N-methyl-D-aspartate (NMDA) receptor antagonists were examined in rats trained to discriminate dizocilpine (0.17 mg/kg, i.p) from saline in a two-lever operant procedure. The dissociative anesthetic-type NMDA antagonists dizocilpine (ED50 0.05 mg/kg), phencyclidine (ED50 3.4 mg/kg) and ketamine (ED50 14 mg/kg) showed complete substitution without producing significant decreases in response rates, whereas dexoxadrol (ED50 4.3 mg/kg) also produced complete substitution with a concomitant decrease (35%) in response rate. Similarly, the low-affinity antagonist memantine resulted in complete substitution (ED50 9.7 mg/kg) at doses that significantly reduced (68%) the response rate. All other low-affinity antagonists resulted in either partial or no substitution for the discriminative stimulus effects of dizocilpine at doses that significantly decreased average response rates. These include (ED50 values in parentheses) remacemide (29 mg/kg), the remacemide metabolite 1,2-diphenyl-2-propylamine (ARL 12495) (14 mg/kg), phencylcyclopentylamine (25 mg/kg), dextromethorphan (46 mg/kg), (+/-)-5-aminocarbonyl-10,11-dihydro -5H-dibenzo-[a,d]cyclohepten-5,10-imine (ADCI; no substitution) and levoxadrol (no substitution). We conclude that low-affinity uncompetitive NMDA antagonists have discriminative stimulus properties distinct from dissociative anesthetic-type uncompetitive NMDA antagonists. The lowest-affinity antagonists show virtually no substitution for dizocilpine, whereas the relatively more potent low-affinity antagonists (such as memantine) exhibit greater substitution, but complete substitution is obtained only at rate-reducing doses.

Topics: Acetamides; Analysis of Variance; Anesthetics, Dissociative; Animals; Conditioning, Operant; Dextromethorphan; Dioxolanes; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Ketamine; Male; Memantine; Phencyclidine; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate

The present study characterized the response of the hypothalamo-pituitary-adrenal axis after the acute administration of enantiomeric pairs of drugs that bind to phencyclidine (PCP) and sigma receptors. Rats were injected with the enantiomers of 1-(1-phenylcyclohexyl)-3-methylpiperidine (PCMP), N-allylnormetazocine (SKF 10,047), dioxadrol (dexoxadrol and levoxadrol) or pentazocine, and plasma levels of adrenocorticotropin (ACTH) and corticosterone were determined by radioimmunoassay. The effects of the enantiomers of PCMP and dioxadrol showed stereospecificity as both (+)-PCMP and dexoxadrol increased plasma levels of ACTH and corticosterone but (-)-PCMP and levoxadrol had no effect. Whereas (-)-pentazocine produced greater responses than (+)-pentazocine, the two enantiomers of SKF 10,047 did not show stereoselectivity. Although the potency of the enantiomers of PCMP and dioxadrol parallel their affinity for binding to PCP receptors, the potency of the enantiomers of pentazocine did not. These results suggest that although the stimulation of the hypothalamo-pituitary-adrenal axis by PCP and drugs with PCP-like activity might be due to interactions with PCP receptors, the effects of pentazocine also involve interactions at other sites.

Topics: Adrenocorticotropic Hormone; Analgesics; Animals; Corticosterone; Dioxolanes; Drug Interactions; Hypothalamo-Hypophyseal System; Injections, Subcutaneous; Male; Phenazocine; Phencyclidine; Piperidines; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Receptors, sigma; Stereoisomerism; Sympathomimetics

The ion channel probe phencyclidine [1-(1-phenylcyclohexyl)piperidine; PCP] selectively inhibited aggregation, secretion and ultrastructural changes in platelets induced by adrenaline, but did not affect activation induced by other common platelet agonists such as alpha-thrombin, ADP, collagen or ionophore A23187. [3H]PCP bound to platelets with high affinity (Kd 134 +/- 33 nM; 3600 +/- 1020 sites/platelet), as did the thienyl analogue [3H]TCP (1-[1-(2-thienyl)cyclohexyl]piperidine). PCP binding to platelets was increased 3-4-fold in N-methylglucamine buffer in the absence of Na+ ions. Binding was unaffected by haloperidol and was only weakly inhibited (EC50 10-20 microM), without significant stereoselectivity by the two sets of stereoselective ligands, dexoxadrol/levoxadrol and (+)MK801/(-)MK801. Binding of PCP was not competed for by adrenaline or yohimbine. Only the high-affinity binding of [3H]PCP to platelets was blocked by prior treatment of the platelets with the covalent affinity probe Metaphit, and these platelets no longer aggregated in response to adrenaline although they responded normally to alpha-thrombin, ADP and collagen. These results suggest that platelets contain high-affinity receptors for PCP that can modulate adrenaline-induced platelet activation.

Topics: Binding, Competitive; Blood Platelets; Cells, Cultured; Chromatography, Gel; Cyclic AMP; Dioxolanes; Dizocilpine Maleate; Epinephrine; Humans; Phencyclidine; Piperidines; Platelet Activation; Receptors, Neurotransmitter; Receptors, Phencyclidine

A series of dioxolane analogues based on dexoxadrol ((4S,6S)-2,2-diphenyl-4-(2-piperidyl)-1,3-dioxolane) and etoxadrol ((2S,4S,6S)-2-ethyl-2-phenyl-4-(2-piperidyl)-1,3-dioxolane) were prepared and tested for their ability to displace [3H]TCP (1-[1-(2-thienyl)cyclohexyl]piperidine) from PCP (1-(1-phenylcyclohexyl)piperidine) binding sites in rat brain tissue homogenates. Qualitative structure-activity relationships within this series were explored through modifications of the three major structural units of dexoxadrol, the piperidine, 1,3-dioxolane, and aromatic rings of the molecule. N-Alkyl derivatives of dexoxadrol were found to be inactive, as were those analogues where the dioxolane ring was modified. Phenyl-substituted etoxadrol analogues were compared to similarly substituted PCP analogues and distinct differences were found in their structure-activity relationships suggesting that the aromatic rings in these two drug classes interact differently with the PCP binding sites. The replacement of the phenyl ring in etoxadrol by either a 2- or 3-thienyl ring led to compounds with affinity comparable to etoxadrol, and the replacement of the ethyl moiety on etoxadrol's dioxolane ring with propyl (7) or isopropyl (8) led to compounds which were more potent than etoxadrol or PCP. The most potent compound was (2S,4S,6S)-2-ethyl- 2-(1-chlorophenyl)-4-(2-piperidyl)-1,3-dioxolane (11), where a chlorine moiety was placed in the ortho position in the aromatic ring of etoxadrol. Its potency was comparable with TCP in vitro.

Topics: Analgesics; Animals; Binding Sites; Brain; Dioxolanes; Phencyclidine; Piperidines; Rats; Structure-Activity Relationship

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.

Topics: Animals; Binding, Competitive; Carbachol; Cerebral Cortex; Dioxolanes; Guinea Pigs; Haloperidol; Ileum; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; N-Methylscopolamine; Parasympatholytics; Pentazocine; Phosphatidylinositols; Piperidines; Receptors, Muscarinic; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Phencyclidine; Scopolamine Derivatives

MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine maleate] and related compounds were studied in monkeys discriminating between 0.032 mg/kg of (+)-MK-801 and saline and in a separate group of monkeys responding under a multiple schedule of repeated acquisition and performance of conditional discriminations. In the drug discrimination study, small doses of (+)-MK-801 occasioned saline-lever responding whereas larger doses occasioned responding on the MK-801 lever. Dexoxadrol substituted completely (greater than or equal to 90%) for the MK-801 discriminative stimulus in all subjects whereas dextrorphan and phencyclidine (PCP) substituted in only two of three subjects. Neither ketamine, (+)-N-allylnormetazocine, dextromethorphan nor the competitive excitatory amino acid antagonist CGS 19755 [cis-4-phosphonomethyl-2-piperidine-carboxylic acid] substituted for MK-801 in any of the monkeys. PCP, dextrorphan, dextromethorphan, (+)- and (-)-MK-801 decreased rates of lever pressing and increased errors in both components of the multiple acquisition, performance schedule. For each compound errors were increased in the acquisition component with doses smaller than doses required to increase errors in the performance component. In both procedures (+)-MK-801 was 10 times more potent than (-)-MK-801, although qualitatively similar results were obtained with the two enantiomers. PCP-like drugs have many effects in common, including their effects on learning and performance; however, with regard to discriminative stimulus effects this does not appear to be a homogenous pharmacological class, suggesting that change in excitatory amino acid-mediated neurotransmission might not be the only mechanism by which MK-801 and related compounds exert behavioral effects in nonhuman primates.

Topics: Analgesics; Animals; Behavior, Animal; Conditioning, Operant; Dextrorphan; Dioxolanes; Discrimination, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Erythrocebus patas; Female; Ketamine; Macaca fascicularis; Macaca mulatta; Male; Phencyclidine; Piperidines; Stereoisomerism

Recently, the presence of two high affinity binding sites for phencyclidine were described in guinea pig brain, with one site coupled to the glutamate excitatory amino acid receptor, specifically activated by N-methyl-D-aspartate (NMDA) (site 1) and the other site associated with the dopamine (DA) reuptake carrier (site 2). Phencyclidine and its analogs, as well as the benzomorphan opiates, are known to interact with binding sites for phencyclidine. In this study, the equilibrium dissociation constants (Kd) of these compounds for the two binding sites for phencyclidine were determined. Phencyclidine and 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), an analog of PCP, were essentially non-selective between the two sites and also were the two drugs of the group observed to have the highest affinity for site 2. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine [(+)MK801] was the most selective agent for site 1, while none of the drugs tested showed selectivity for site 2. In humans, phencyclidine produces psychotomimetic effects, while (+)MK801 has been reported to produce minimal, if any, psychotomimetic effects, at doses sufficient to reduce seizures. These clinical observations, in conjunction with the present biochemical binding data, suggest that (+)MK801 may serve as a "marker" for site 1 and that the psychotomimetic effects of phencyclidine might be mediated by site 2.

Topics: Analgesics; Animals; Benzomorphans; Brain; Dioxolanes; Dizocilpine Maleate; Guinea Pigs; In Vitro Techniques; Kinetics; Ligands; Narcotics; Phencyclidine; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Phencyclidine; Structure-Activity Relationship

At concentrations greater than or equal to 100 microM, phencyclidine (PCP), N-(1-(2-thienyl)-cyclohexyl)piperidine (TCP), and MK-801 induced [3H]dopamine release from dissociated cell cultures of rat mesencephalon. This release was Ca2+ independent and tetrodotoxin insensitive. Tetrodotoxin (2 microM) itself had no effect on spontaneous release of [3H]dopamine. [3H]Dopamine release was induced by 1,3-di(2-tolyl)guanidine, a sigma ligand, and by 4-aminopyridine (1-3 mM), a K+ channel blocker. No stereoselectivity was observed for [3H]dopamine release evoked by the dioxadrol enantiomers, dexoxadrol, and levoxadrol, or by enantiomers of N-allylnormetazocine (SKF 10,047). The selective dopamine uptake inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909) did not affect spontaneous or TCP-evoked [3H]dopamine release. Together, these data suggest that the dopamine-releasing effects of PCP-like compounds on the mesencephalic cells were not mediated by actions at the PCP receptor or sigma binding site, Ca2+, or Na+ channels, or at the high affinity dopamine uptake site. It remains conceivable that blocking actions of PCP-like compounds at voltage-regulated K+ channels may at least partly explain the response. These results are discussed in comparison with findings in intact brain.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Binding Sites; Cells, Cultured; Dioxolanes; Dizocilpine Maleate; Dopamine; Dose-Response Relationship, Drug; Guanidines; Mesencephalon; N-Methylaspartate; Neurotransmitter Uptake Inhibitors; Phencyclidine; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Phencyclidine; Sigma Factor; Tritium

The purpose of this experiment was to investigate the interactions of norepinephrine with PCP (phencyclidine) and sigma receptor agonists--modulated GABA (gamma aminobutyric acid) response in the cerebellum. Drugs were directly applied to a single cerebellar Purkinje neuron of urethane-anesthesitized rat through a multibarrel pipette. (+)PCMP [1-(-1-phenylcyclohexyl)-3-methyl piperidine], a PCP receptor agonist, and dexoxadrol, a sigma receptor agonist, significantly enhanced GABA induced inhibition. In norepinephrine-depleted animals, however, both (+)PCMP and dexoxadrol did not modulate GABA's effect. In conclusion, our findings indicated that the PCP/sigma-induced facilitation of GABA reactions were mediated through noradrenergic system in the cerebellum.

Topics: Animals; Cerebellum; Dioxolanes; Electrophysiology; gamma-Aminobutyric Acid; Male; Norepinephrine; Phencyclidine; Piperidines; Purkinje Cells; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma

The effect of phencyclidine (PCP) on carbachol-induced phosphoinositol hydrolysis was examined in rat brain slices taken from cortex, caudate-putamen and hippocampus. In all three regions studied, PCP significantly inhibited carbachol-induced [3H]inositol phosphate accumulation working as low as 10(-6) M in the cerebral cortex. Because PCP has been shown to act at two sites, a PCP-site and a sigma site, various PCP-like agonists [levoxadrol (Lev), dexoxadrol (Dex) and MK-801 [(+)-5-methyl-10,11-dihydro- 5H-dibenzo(a,b)cyclo-hepaten-5, 10-imine maleate]] as well as sigma agonists [(+)-SKF10047 and 1,3-di(2-toly)guanidine (DTG) were examined for their effects on carbachol-induced phosphoinositol hydrolysis. All but MK-801 significantly inhibited the carbachol action; however, their order of potencies, Lev greater than or equal to Dex much greater than PCP greater than or equal to DTG greater than or equal to (+)-SKF10047 differed from those of other known PCP interactions at PCP and sigma sites. Inasmuch as it is known that PCP competes for binding at muscarinic sites, we examined the effects of PCP, Lev, Dex, DTG and MK-801 on the binding of L-[3H]-3-quinuclidinyl benzilate to its muscarinic site. All blocked L-[3H]-3-quinuclidinyl benzilate binding and exhibited a rank order of potency almost identical to that obtained in the inositol studies with Lev greater than Dex much much greater than DTG much greater than PCP MK-801. In addition, the IC50 values obtained from both studies were very similar. It is concluded that PCP, PCP-like compounds and sigma agonists block carbachol-induced inositol-phosphate accumulation by blockade of muscarinic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Carbachol; Culture Techniques; Dibenzocycloheptenes; Dioxolanes; Dizocilpine Maleate; Inositol Phosphates; Male; Phenazocine; Phencyclidine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Muscarinic; Sigma Factor; Transcription Factors

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.

Topics: Analgesics; Animals; Dioxolanes; Evoked Potentials; Hippocampus; Male; Phencyclidine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Phencyclidine

Some of the dioxolanes produce pharmacological effects that have much in common with phencyclidine and phencyclidine-like drugs. Dioxadrol can be resolved into two enantiomers, dexoxadrol and levoxadrol. Dexoxadrol has an affinity for phencyclidine receptors that is much greater than that of levoxadrol, but dexoxadrol and levoxadrol have nearly equal affinities for sigma receptors. The systematic analysis of the relative potencies of dexoxadrol and levoxadrol can be used as an approach to define effects mediated by phencyclidine vs sigma receptors. Compounds that act on phencyclidine receptors, as well as affecting behavior, alter body temperature in the rat. The purpose of the present study was to compare and contrast the effects of the acute administration of dexoxadrol, levoxadrol, MK-801 and phencyclidine on body temperature in the rat. Dexoxadrol and levoxadrol (5.0, 10.0, 20.0 or 40.0 mg/kg), MK-801 (0.12, 0.6 or 1.2 mg/kg) or phencyclidine (5.0, 10.0 or 20.0 mg/kg) were administered subcutaneously and body temperature was measured. Both dexoxadrol and MK-801 produced hyperthermia but levoxadrol did not affect body temperature. In contrast to the hyperthermic effects of dexoxadrol and MK-801, phencyclidine produced hypothermia. These findings indicate that hypothermia induced by phencyclidine is not due to interactions with phencyclidine receptors and, while dexoxadrol, MK-801 and phencyclidine may share some similar receptor binding and behavioral characteristics, they can be differentiated on the basis of their effects on body temperature.

Topics: Animals; Body Temperature; Dibenzocycloheptenes; Dioxolanes; Dioxoles; Dizocilpine Maleate; Injections, Subcutaneous; Male; Phencyclidine; Piperidines; Rats; Rats, Inbred Strains; Time Factors

The purpose of this experiment was to investigate the interaction of GABA (gamma aminobutyric acid) with PCP (phencyclidine) and sigma receptor agonists in the cerebellum. Drugs were applied directly to a single cerebellar Purkinje neuron of urethane-anesthetized rats, through a multibarrel pipette. The PCP receptor agonist, (+)PCMP [1-(-1-phenylcyclohexyl)-3-methyl piperidine], significantly enhanced GABA-induced inhibition. On the other hand, its stereoisomer, (-)PCMP, had no such modulatory effect. Dexoxadrol, a sigma receptor agonist, similar to (+)PCMP, potentiated GABA-induced depression. Its stereoisomer, levoxadrol, although inhibiting the spontaneous firings of Purkinje neurons, did not alter the effect of GABA. In conclusion, the findings indicate that the electrophysiological mechanisms of PCP-induced facilitation of GABA-induced reactions are similar to those triggered by sigma agonists in the cerebellum.

Topics: Analgesics; Animals; Cerebellum; Depression, Chemical; Dioxolanes; Dioxoles; Electrophysiology; gamma-Aminobutyric Acid; Heart Conduction System; In Vitro Techniques; Male; Neurons; Phencyclidine; Piperidines; Purkinje Fibers; Rats; Rats, Inbred Strains; Stereoisomerism; Sympathomimetics

We investigated the effects of phencyclidine (PCP), a psychotomimetic dissociative anesthetic, and several related drugs on voltage-dependent K+ currents in PC12 cells, a neuron-like clonal cell line derived from a rat pheochromocytoma. Whole-cell voltage clamp recordings demonstrated two kinetically distinct voltage-dependent outward (K+) current components in these cells: a rapidly activating and inactivating component, IA, that was selectively eliminated by 4-aminopyridine (2 mM) and a slowly activating, minimally inactivating (sustained) component, IK, that was specifically blocked by tetraethylammonium (20 mM). PCP (1-100 microM) produced a dose-dependent blockade of both IK and IA, however, at low doses the drug selectively reduced IK with little effect on IA; the IC50s for blockade of IK and IA were 4 and 25 microM, respectively. The blockade of IK was voltage-dependent so that the degree of block decreased with increasing depolarization, indicating that the blocking mechanism is likely one in which the positively charged PCP molecule is drawn into the channel pore. Several PCP related drugs also suppressed IK. Thienyl-PCP (TCP), a drug that is behaviorally more potent than PCP, partially blocked IK at low doses (31% at 1 microM), but even at high doses (25 microM) the degree of block was never as great as that produced by PCP. The optically active PCP congeners (+)-PCMP (1-(1-phenylcyclohexyl)-3-methyl-piperidine) and dexoxadrol were also potent blockers of IK. However, in contrast to the stereospecificity these compounds demonstrate in binding to high-affinity PCP receptors and in eliciting PCP-like behavioral responses, their enantiomers (-)-PCMP and levoxadrol showed similar potencies as the parent compounds in blocking IK. These results demonstrate that PCP and related drugs are powerful, selective blockers of IK in PC12 cells. The structure-activity studies indicate that this effect occurs at a site that is pharmacologically distinct from the behaviorally relevant PCP receptor. Blockade of K+ channels is unlikely to be responsible for the psychotomimetic or anti-convulsant properties of PCP, but could account for the convulsant potential of the drug.

Topics: Anesthetics; Animals; Dioxolanes; Electric Stimulation; Ion Channels; Membrane Potentials; Phencyclidine; Pheochromocytoma; Piperidines; Potassium; Rats; Tumor Cells, Cultured

The PCP-like compounds ketamine and dexoxadrol were evaluated in two behavioral test procedures known to be sensitive to competitive N-methyl-D-aspartate (NMDA) receptor antagonists. In the NMDA-induced convulsion test in mice, ketamine and dexoxadrol blocked convulsant activity only at doses that also induced nonspecific effects of PCP-like behaviors, thereby confounding the interpretation of results. These compounds also blocked NMDA-induced discriminative stimuli in rats; however, this effect was produced at doses lower than those which induced the nonspecific behavioral effects. These results provide evidence that in behavioral procedures, PCP-like compounds may block excitatory amino acid receptor stimulation by NMDA. The NMDA discrimination identifies these interactions without the influence of motor deficit or other behavioral motor effects.

Topics: Animals; Aspartic Acid; Behavior, Animal; Dioxolanes; Dioxoles; Ketamine; Male; Mice; Motor Activity; N-Methylaspartate; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

The effects of phencyclidine (PCP) and two dioxolane stereoisomers, dexoxadrol and levoxadrol, on hippocampal inhibition were compared. Field potentials were recorded in the CA1 pyramidal cell layer in the rat hippocampal slices in vitro. Recurrent inhibition of the population spikes evoked orthodromically by stimulation of the Schaffer collaterals was induced by antidromic conditioning stimulation at appropriate time intervals before the orthodromic stimulation. The drugs were applied by micropressure ejection in concentrations which did not affect the unconditioned population spike. After PCP or dexoxadrol administration, the orthodromically evoked population spike was much less reduced by the antidromic conditioning stimulation than before, suggesting that the recurrent inhibition was diminished. Levoxadrol had only negligible effect. Since dexoxadrol has many PCP-like pharmacological properties but levoxadrol does not, we concluded that PCP attenuates hippocampal recurrent inhibition by activating the PCP receptors. It is suggested that this action results in depression of excitatory synaptic transmission from axon collaterals to the inhibitory interneuron with possible involvement of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor.

Topics: Analgesics; Animals; Dioxolanes; Hippocampus; In Vitro Techniques; Male; Phencyclidine; Piperidines; Pressure; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Phencyclidine

1. Efflux of 86Rb from synaptosomes prepared from rat forebrain was used to assess voltage-gated changes in K+ permeability in mammalian central nerve terminals. 2. Although they are structurally unrelated to phencyclidine (PCP), the sigma-ligands, N-allyl-normetazocine (NANM; SKF 10,047) and cyclazocine, generalize to PCP in behavioral assays, displace [3H]PCP from a high-affinity binding site in brain, and potently block the same voltage-gated K+ channel as PCP itself. 3. The block of the voltage-gated K+ channel in nerve terminals by NANM and cyclazocine was stereoselective and was unaffected by the opioid antagonist naloxone. Moreover, in our experiments the relative activity of the stereoisomers of NANM and cyclazocine compared favourably with their relative activity in behavioural paradigms and binding assays. 4. Dexoxadrol, the D-isomer of dioxodrol, which produces PCP-like behavioural effects and displaces bound [3H]PCP, was a potent blocker of the PCP-sensitive, voltage-gated K+ channel. The corresponding L-isomer, levoxadrol, which produces morphine-like antinociception and sedation, but does not produce PCP-like behaviour nor displace bound [3H]PCP, was a very weak blocker of the voltage-gated K+ channel. 5. Levoxadrol, but not dexoxadrol, activated a separate K+ channel, as manifested by an increase in 86Rb efflux. This effect was blocked by naloxone. 6. We conclude that one of the PCP-sigma-ligand binding sites in the brain may be associated with the voltage-gated, non-inactivating K+ channel we observe in nerve terminals. Our findings are also consistent with the view that some of the behavioural manifestations of PCP intoxication are mediated by block of presynaptic K+ channels.

Topics: Animals; Brain; Cyclazocine; Dioxolanes; Dioxoles; Dose-Response Relationship, Drug; Hallucinogens; In Vitro Techniques; Naloxone; Phenazocine; Phencyclidine; Piperidines; Potassium Channels; Rats; Synaptosomes

Dioxadrol exists in four isomeric forms. alpha-(+)-Dioxadrol (dexoxadrol) showed phencyclidine (PCP)-like activity in rhesus monkeys trained to discriminate s.c. administration of ketamine, but neither alpha-(-)-dioxadrol (levoxadrol) nor beta-(+/-)-dioxadrol showed such activity. In addition, response-contingent i.v. dexoxadrol maintained higher rates of responding than either levoxadrol or beta-dioxadrol in monkeys experienced with ketamine self-administration. The order of potency in displacing bound 1-[1-(2-thienyl)cyclohexyl]piperidine from binding sites in rat brain homogenates was dexoxadrol much greater than levoxadrol = beta-(+/-)-dioxadrol. Viewed in the context of previous studies with stereochemical probes of the PCP receptor, these results extend and confirm the supposition that dexoxadrol and levoxadrol are the stereochemical probes of choice in the study of effects mediated through PCP receptors. The absolute configuration of dexoxadrol was determined to be 4S, 6S by X-ray crystallography, thus defining the optimum chirality necessary for receptor binding and PCP-like activity in the dioxadrol series. Based on these and other considerations, receptor-active conformations of dexoxadrol and PCP are proposed.

Topics: Analgesics; Animals; Brain; Dioxolanes; Dioxoles; Discrimination, Psychological; Isomerism; Ketamine; Kinetics; Macaca mulatta; Models, Molecular; Molecular Conformation; Phencyclidine; Piperidines; Receptors, Neurotransmitter; Receptors, Phencyclidine; Self Administration; Stereoisomerism; Structure-Activity Relationship

In each of two components of a multiple schedule, patas monkeys were required to respond on a right or left lever depending upon the stimulus combination (a color and a geometric form) presented. Reinforcement of a response in the presence of one stimulus (the form) was conditional upon the other stimulus (the color). The completion of a two-member chain of discriminations produced a food pellet. Errors produced a brief timeout. One component of the multiple schedule was a repeated-acquisition task in which the discriminative stimuli for left- and right-lever responses changed each session (learning). In the other component, the discriminative stimuli were the same each session (performance). Dose-effect curves were determined for the kappa agonists bremazocine, tifluadom, ethylketocyclazocine and U50488H. Each drug produced dose-related decreases in overall response rate but had little or no effect on accuracy in either learning or performance. The rate-decreasing effects of ethylketocyclazocine and tifluadom were due to a dose-related pause at the start of the session, whereas those of bremazocine and U50488 were due largely to sporadic pausing throughout the session. Naltrexone blocked the effects of each drug whereas quaternary naltrexone had no effect. In contrast to the kappa agonists, dexoxadrol produced a dose-related disruption in accuracy of responding in learning. Dexoxadrol also decreased response rate in both acquisition and performance in a dose-related manner. Naltrexone attenuated the effects of low doses of dexoxadrol on accuracy, but failed to block the disruptive effects of higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analgesics; Animals; Benzomorphans; Conditioning, Psychological; Cyclazocine; Dioxolanes; Dioxoles; Discrimination Learning; Dose-Response Relationship, Drug; Erythrocebus patas; Ethylketocyclazocine; Female; Macaca fascicularis; Male; Naltrexone; Piperidines; Receptors, Opioid; Receptors, Opioid, kappa

The interactions of phencyclidine (PCP) and related agonists with putative receptor blockers were studied on cerebellar Purkinje neurons using electrophysiological techniques. Depressions induced by PCP or dexoxadrol, a sigma receptor agonist, were markedly antagonized by the PCP receptor antagonist metaphit, which acylates PCP receptors via its isothiocyanate moiety. Conversely, the depressant effect of levoxadrol, the (-) isomer of dexoxadrol, was not affected by metaphit. Further evidence that metaphit's specific antagonism of dexoxadrol- and PCP-mediated depressions was derived from data showing that drugs which respectively acylate mu and delta opioid receptors, benzimidazole isothiocyanate and fentanyl isothiocyanate, do not antagonize the actions of either PCP or dexoxadrol. Moreover, tyramine, which like PCP acts as an indirect norepinephrine agonist, is not antagonized by metaphit. These observations support the concept that metaphit causes a pharmacologically specific and irreversible antagonism of the effects of both PCP and dexoxadrol in the cerebellum. Thus, the electrophysiological mechanisms of PCP actions are similar to those triggered by sigma opioid agonists in this brain area.

Topics: Animals; Cerebellum; Dioxolanes; Drug Interactions; Electrophysiology; Isomerism; Male; Phencyclidine; Piperidines; Purkinje Cells; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Substrate Specificity

The effects of representative drugs from three classes of psychotomimetic compounds (arylcyclohexylamines, benzomorphan opioids and dioxolanes) have been examined on synaptic transmission at an identified monosynaptic pathway in rat hippocampal slices. The compounds tested were phencyclidine (PCP) and ketamine, the racemate and isomers of SKF 10,047 (N-allylnormetazocine), and the isomers of dioxadrol (dexoxadrol and levoxadrol). In the absence of added magnesium ions (Mg) in the perfusion medium low frequency stimulation of the Schaffer collateral-commissural pathway evoked a burst of population spikes in the CA1 cell body region. The secondary components of this response could be abolished by the selective N-methyl-D-aspartate (NMDA) antagonist D-2-amino-5-phosphonovalerate (APV). PCP (1 microM) or ketamine (10 microM) selectively blocked the secondary components of the synaptic response. The effect of PCP was neither mimicked nor prevented by hexamethonium and atropine, phentolamine and propranolol, or clonidine and was therefore unlikely to involve cholinergic or adrenergic neurotransmitter systems. The sigma opiate, (+/-)-SKF 10,047 (10 microM) also abolished selectively the secondary components of the synaptic response. There was no apparent difference between the potency of the stereoisomers of this compound. The action of (+/-)-SKF 10,047 was not affected by either naloxone or haloperidol, indicating that this effect did not involve opioid receptors or the haloperidol-sensitive sigma site. Dexoxadrol (10 microM), but not levoxadrol (10 microM), also selectively blocked the secondary components of the synaptic response. It is concluded that these psychotomimetic agents can block an NMDA receptor-mediated component of synaptic transmission in the hippocampus and that this effect is mediated by a specific PCP/sigma site.

Topics: Analgesics; Animals; Dioxolanes; Hallucinogens; Hippocampus; In Vitro Techniques; Ketamine; Kinetics; Magnesium; Neuromuscular Depolarizing Agents; Phenazocine; Phencyclidine; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Synapses; Synaptic Transmission

The effects of 3, structurally unrelated sigma agonist compounds on local cerebral glucose utilization (LCGU) were compared. The common effects of sigma agonist compounds on LCGU included a moderate, global elevation of LCGU. Superimposed upon this elevation were larger increases in LCGU occurring mainly in components of the limbic system, and the pyramidal and extrapyramidal motor systems. The only structures whose metabolic rates were significantly elevated by all 3 compounds were the frontal cortex and the anterior cingulate cortex. The altered metabolic activity in these limbic brain regions may underly the psychotomimetic effects produced by sigma agonist compounds.

Topics: Animals; Brain; Dioxolanes; Dioxoles; Glucose; Hallucinogens; Male; Phenazocine; Phencyclidine; Piperidines; Rats; Rats, Inbred Strains

Photoaffinity labeling of rat brain phencyclidine (PCP) receptors with [3H] azido phencyclidine ([3H]AZ-PCP) reveals the existence of five polypeptides which are specifically labeled by the affinity probe (Mr's 90,000, 62,000, 49,000, 40,000 and 33,000). These labeled components are unevenly distributed in rat brain. In the frontal cortex, thalamus and olfactory bulb, the major bands labeled are the Mr's 90 K and 62 K polypeptides; in the cerebellum most of the labeling is in the 90 K and 33 K bands; and in the hippocampus all but the Mr 40 K band are heavily labeled. Together with dexoxadrol/[3H]PCP competition binding data, which indicated the existence of high and low affinity dexoxadrol/PCP binding sites, these results suggest regional heterogeneity of PCP receptors. The regional distribution of the high affinity dexoxadrol binding sites correlates best with that of the Mr 90 K polypeptide.

Topics: Affinity Labels; Animals; Azides; Binding, Competitive; Brain; Dioxolanes; Electrophoresis, Polyacrylamide Gel; Peptides; Phencyclidine; Piperidines; Rats; Receptors, Neurotransmitter; Receptors, Phencyclidine; Synaptosomes

[3H]dexoxadrol, a dissociative anesthetic, binds with high affinity to specific sites in rat brain (membrane binding and light microscopic autoradiography). Various phencyclidine (PCP) analogues compete for [3H]dexoxadrol sites in a slightly different manner than against [3H]PCP binding sites. As for [3H]PCP binding, [3H]dexoxadrol binding sites are highly concentrated in brain regions such as the cortex and the hippocampus. However, other areas such as the hypothalamus are enriched only in [3H]dexoxadrol binding sites. This suggests that [3H]dexoxadrol binds to PCP-related sites in certain brain regions but not in others. In the human forebrain, [3H]dexoxadrol binding sites are distributed as in the rat brain and mainly found in the caudate, putamen and cortex.

Topics: Animals; Autoradiography; Binding Sites; Brain; Dioxolanes; Dioxoles; Humans; Membranes; Phencyclidine; Piperidines; Rats

Topics: Anesthetics; Animals; Batrachotoxins; Brain; Chemical Phenomena; Chemistry; Dioxolanes; Dioxoles; Discrimination Learning; Humans; Macaca mulatta; Phencyclidine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Phencyclidine

Phencyclidine (PCP), a semirigid molecule containing a cyclohexane ring with vicinally attached aromatic and piperidine rings, produces characteristic discriminative stimulus properties and pupillary miosis in rats. The effectiveness of a series of aromatic and nitrogen substituted analogs of PCP in producing PCP-like discriminative stimuli and changes in pupil diameter was determined in rats trained to discriminate between saline and 3.0 mg/kg of PCP. Dexoxadrol and its optical isomer levoxadrol were also evaluated for purposes of comparison. Analogs in which the electron-density of the aromatic ring was increased (3NH2-PCP) or only slightly reduced (3F-PCP) retained PCP-like activity. A loss of PCP-like activity occurred with analogs in which the electron-density of the aromatic ring was greatly reduced (3NO2-PCP) or extended to a larger system (1NCP and 2NCP). PCP-like activity also was abolished in analogs in which the distance between the aromatic ring and the remainder of the molecule was systematically increased by one, two or three methylene units. In contrast, substitutions on the nitrogen atom altered the potency, but not the efficacy, of such analogs. Dexoxadrol produced PCP-like activity whereas its optical enantiomer levoxadrol was devoid of such activity. These findings suggest a drug receptor surface with multiple domains or subsites which recognize regions of structural overlap among the phencyclidines, dioxolanes and psychotomimetic benzomorphan derivatives.

Topics: Animals; Dioxolanes; Discrimination, Psychological; Male; Phencyclidine; Piperidines; Pupil; Rats; Rats, Inbred F344; Stereoisomerism; Structure-Activity Relationship

Pigeons were trained to discriminate between dextrorphan (10 mg/kg) and saline in a task in which 20 consecutive key pecks on either the left or right key, depending on whether dextrorphan or saline had been administered, produced food. During sessions in which stimulus generalization to other drugs was evaluated, 20 consecutive responses on either the dextrorphan- or saline-appropriate key produced food. Dextromethorphan and dexoxadrol produced dose-related stimulus control of behavior similar to that produced by dextrorphan. In contrast, the l-isomers of these compounds, levomethorphan, levoxadrol and levorphanol, at doses up to and including those that markedly decreased the rate of responding, produced responding primarily on the saline-appropriate key. In addition, both the d- and l-isomers of methadone, codeine, morphine, butorphanol and profadol resulted in predominantly saline-appropriate responding. l-Cyclorphan, dl-, l- and d-SKF-10,047 and l- and d-cyclazocine produced dose-related dextrorphan-appropriate responding, whereas, l-oxilorphan (the 14-hydroxymorphinan analog of cyclorphan), dl-, l- and d-pentazocine, l- and d-ethylketazocine and l-naltrexone resulted in either responding exclusively on the saline-appropriate key or responding that was intermediate between that appropriate for saline and dextrorphan. Although levorphanol alone produce little or no dextrorphan-appropriate responding, the coadministration of naltrexone (1.0 mg/kg) and high doses of levorphanol, but not levoxadrol, resulted in responding similar to that produced by dextrorphan.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bemegride; Binding Sites; Columbidae; Dextrorphan; Dioxolanes; Discrimination Learning; Dose-Response Relationship, Drug; Drug Interactions; Generalization, Stimulus; Morphinans; Naltrexone; Pentobarbital; Piperidines; Stereoisomerism; Structure-Activity Relationship

Topics: Animals; Conditioning, Operant; Dioxolanes; Dioxoles; Discrimination, Psychological; Macaca mulatta; Male; Phencyclidine; Piperidines; Reinforcement, Psychology; Saimiri; Self Administration

The effects of phencyclidine, etoxadrol and dexoxadrol were compared in pigeons responding under a multiple fixed-ratio 30-response, fixed-interval 5-minute schedule of grain presentation. Etoxadrol was half as potent as phencyclidine in suppressing responding, and dexoxadrol was half as potent as etoxadrol. These three drugs, along with ketamine and cyclazocine, were also compared in pigeons trained to discriminate injections of 0.64 mg/kg of phencyclidine from injections of distilled water. All five drugs produced phencyclidine-like responding at the higher doses, with the order of potency being phencyclidine, etoxadrol, cyclazocine, dexoxadrol and ketamine. These data showed that a phencyclidine-like discriminative cue can be demonstrated across three classes of chemical compounds, as exemplified by phencyclidine and ketamine, etoxadrol and dexoxadrol, and cyclazocine.

Topics: Analgesics; Animals; Columbidae; Conditioning, Operant; Cyclazocine; Dioxolanes; Dioxoles; Discrimination Learning; Dose-Response Relationship, Drug; Ketamine; Male; Phencyclidine; Piperidines; Reinforcement Schedule

Rats trained to discriminate between phencyclidine and saline vehicle were used to test various agents for their ability to mimic or block the phencyclidine cue. ketamine, dexoxadrol, tiletamine, and phencyclidine analogs were found to mimic phencyclidine's behavioral effects. Treatment with the adenosime receptor agonists N6-cyclohexyladenosine and L-phenylisopropyladenosine blocked the discriminative properties of phencyclidine. These results suggest that adenosine receptor agonists might be useful in treating phencyclidine-induced psychosis.

Topics: Adenosine; Animals; Dioxolanes; Humans; Ketamine; Phencyclidine; Phencyclidine Abuse; Piperidines; Rats; Receptors, Cell Surface; Receptors, Purinergic; Tiletamine