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PubMed2003

Potent sigma 1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine provides ischemic neuroprotection without altering dopamine accumulation in vivo in rats.

The in vivo signaling of ischemic neuroprotection provided by sigma-receptor ligands remains unclear. Catecholamines have been implicated in the propagation of ischemic neuronal injury, and previous in vitro studies suggest that sigma ligands modulate dopaminergic neurotransmission. In this study, we tested the hypothesis that the potent sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) attenuates the increase of extracellular dopamine in ischemic striatum. Under controlled physiological conditions, a microdialysis probe was implanted in right caudoputamen (CP) complex of adult male Wistar rats. Rats were subjected to 2 h of transient middle cerebral artery occlusion (MCAO) by the intraluminal suture technique. In a blinded, randomized fashion, rats were divided into five treatment groups: Group 1 (n = 8; saline-saline) continuous i.v. infusion of saline vehicle 30 min before MCAO followed by saline at reperfusion until the end of the experiment; Group 2 (n = 8; PPBP-PPBP) i.v. PPBP 30 min before MCAO followed by 1 micromol x kg(-1) x h(-1) of PPBP; Group 3 (n = 8; saline-PPBP) i.v. saline before MCAO followed by PPBP; Group 4 (n = 4) surgical shams (saline-saline); and Group 5 (n = 4) surgical shams (PPBP-PPBP). Infarction volume at 22 h of reperfusion in the CP complex (percentage of ipsilateral structure) was significantly attenuated in rats treated with PPBP-PPBP (27.3% +/- 9.1%) and saline-PPBP (27.8% +/- 12.7%) compared with saline-saline (59.3% +/- 7.3%) treatment. There was a three- to fourfold increase in dopamine concentrations in the microdialysates within 40 min of the onset of MCAO. Dopamine and its metabolites dihydroxy phenylacetic acid and homovallinic acid levels were similar among the three groups subjected to MCAO. Therefore, PPBP provides significant ischemic neuroprotection in the CP complex without altering the acute accumulation of dopamine in vivo during transient focal ischemia in the rat.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1972

Inhibition of Sterol Biosynthesis by 2-Isopropyl-4-dimethylamino-5-methylphenyl-1-piperidine Carboxylate Methyl Chloride in Tobacco and Rat Liver Preparations.

2-Isopropyl-4-dimethylamino-5-methylphenyl-1-piperidine carboxylate methyl chloride, 90%, applied to rootless tobacco (Nicotiana tabacum cv. Samson) seedlings inhibits the incorporation of (14)C-mevalonate into sterols. Concomitantly, the retardant causes the accumulation of squalene-2,3-epoxide, an intermediate in sterol biosynthesis. The results with tobacco are identical to those produced by the retardant in cell-free rat liver preparations.

Journal Article↗
PubMed1973

Cholinesterases from Plant Tissues: II. Inhibition of Bean Cholinesterase by 2-Isopropyl-4-dimethylamino-5-methylphenyl-1-piperidine Carboxylate Methyl Chloride (AMO-1618).

2-Isopropyl-4-dimethylamino-5-methylphenyl-1-piperidine carboxylate methyl chloride (AMO-1618) inhibits the activity of a cholinesterase isolated from mung bean (Phaseolus aureus) roots at concentrations comparable to those which retard growth and inhibit development of secondary roots of bean seedlings. Fifty per cent inhibition of the cholinesterase activity occurred at 0.21 mm. Inhibition of the cholinesterase is non-competitive and irreversible. The growth retardant seems to be a specific cholinesterase inhibitor since it has no effect on non-choline esterases.

Journal Article↗
PubMed2002

16-[3-Methoxy-4-(2-piperidin-1-ylethoxy)benzylidene]-17-oxoandrost-5-en-3beta-yl acetate monohydrate.

The title compound, C(36)H(49)NO(5).H(2)O, has the outer two six-membered rings of the steroid nucleus in chair conformations. The central ring B of the steroid nucleus is in an 8beta,9alpha-half-chair conformation, while ring D of the steroid adopts a slightly distorted 13beta,14alpha-half-chair conformation. The piperidine ring is in a chair conformation. The methoxybenzylidene moiety has an E configuration with respect to the carbonyl group at position 17. Intermolecular O-H.O and O-H.N hydrogen bonds link the steroid and water molecules into chains which run parallel to the b axis.

Journal Article↗
PubMed2006

4-acetamido-3,3,5,5-[2H4]-2,2,6,6-tetra([2H3]methyl)piperidin-1-yloxyl 0.33-hydrate.

The asymmetric unit of the title compound, C11H5D16N2O(2).0.33H2O, is formed by three crystallographically independent piperidin-1-yloxyl molecules and a molecule of water. The molecules are crosslinked by nine hydrogen bonds into layers parallel with the ac plane. The water molecule contributes to the stability of the low-symmetry arrangement by four hydrogen bonds.

Journal Article↗
PubMed2001

Studies of molecular structure parameters of 20-piperidin-2-yl-5alpha-pregnan-3beta,20-diol and its N-methyl derivative: two inhibitors of Delta24(25) sterol methyl transferase and Delta24(24') sterol methyl reductase of Trypanosoma cruzi.

Molecular structural parameters of two potential drugs against Trypanosoma cruzi epimastigotes, 20-piperidin-2-yl-5alpha-pregnan-3beta,20-diol (1) and 20-N-methylpiperidin-2-yl-5alpha-pregnan-3beta, 20-diol (2) were studied using a combination of a stereoselective synthetic route, spectroscopic characterization and single-crystal X-ray analysis. Both compounds were synthesized with an R configuration at C20. This chirality is a consequence of the stereoselectivity observed during the formation of the intermediate 20-pyridin-2-yl-5alpha-pregnan-3beta,20R-diol (4). NMR data indicated that the six-membered aza ring of (2) is conformationally more restrained, in CDCl3 solution, than (1). X-ray studies showed that maximum deviations among structural molecular parameters of (1) and (2) correspond to torsion angles along the C20-C22 bonds, leading to a different relative orientation of the N atom; a critical structural parameter for the binding properties of aza-sterols to Delta(24(25)) sterol methyl transferase. Cremer-Pople parameters of the five-membered rings of (1) and (2) lie in the observed range for a family of tetracyclic fused ring systems retrieved from the CSD. The phi2 parameter of (1) lies just on the mean of the family, while phi2 of (2) deviates significantly towards the lower limit.

Animals↗
PubMed1981

Antagonism of excitatory amino acid-induced and synaptic excitation of spinal neurones by cis-2,3-piperidine dicarboxylate.

In tests on neurones in the cat spinal cord in vivo, and frog and immature rat spinal cord in vitro, cis-2,3-piperidine dicarboxylate (cis-2,3-PDA) produced the following effects: (1) selective antagonism of amino acid-induced responses, compared with responses to other putative transmitters; (2) effective antagonism of kainate and quisqualate-induced responses in addition to responses induced by N-methyl-D-aspartate (NMDA) and other excitatory amino acids; (3) partial NMDA-like agonist action; (4) antagonism of dorsal root-evoked excitation of Renshaw cells; (5) potentiation of acetylcholine- and ventral root-evoked excitation of Renshaw cells. This unique spectrum of action may be useful for transmitter receptor characterization in the vertebrate central nervous system.

Alanine↗
PubMed1990

[3H]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine ([3H]TCP) binding in human frontal cortex: decreases in Alzheimer-type dementia.

We studied [3H]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine [( 3H]TCP) binding to human frontal cortex obtained at autopsy from 10 histologically normal controls and eight histopathologically verified cases with Alzheimer-type dementia (ATD). Extensively washed membrane preparations were used to minimize the effects of endogenous substances. In ATD frontal cortex, the total concentration (Bmax) of [3H]TCP binding sites was significantly reduced by 40-50%. The apparent dissociation constant (KD) values showed no significant change. The reduction in binding capacity was also apparent in Triton X-100-treated membrane preparations, and there was a linear correlation between the number of [3H]TCP binding sites and that of N-methyl-D-aspartate (NMDA)-sensitive [3H]glutamate binding sites. [3H]TCP binding sites spared in ATD brains retained the affinity for the ligand and the reactivity to NMDA, L-glutamate, and glycine. These results suggest that the primary change in NMDA receptor-ion channel complex in ATD brains is the reduction of its number, possibly reflecting the loss of neurons bearing these receptor complexes, and that the functional linkage within the receptor complexes spared in ATD brains remains normal.

Alzheimer Disease↗
PubMed1991

A comparison of [3H]MK-801 and N-[1-(2-thienyl)cyclohexyl]-3,4-[3H]piperidine binding to the N-methyl-D-aspartate receptor complex in human brain.

The binding of (+)-[3H]5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate ([3H]MK-801) and N-[1-(2-thienyl)cyclohexyl]-3,4-[3H]piperidine ([3H]TCP) to the N-methyl-D-aspartate (NMDA) receptor complex of human brain has been investigated. Significant differences were noted between the binding of the two ligands in the same tissue samples. Binding of both ligands was stimulated by addition of glutamic acid or glycine. However, addition of both compounds resulted in an additional effect with [3H]MK-801 but not [3H]TCP binding. Saturation analysis revealed approximately twice as many high-affinity sites for [3H]MK-801 (Bmax, 1,500 +/- 300 fmol/mg of protein) than for [3H]TCP (Bmax, 660 +/- 170 fmol/mg of protein). In addition, a low-affinity site was detected for [3H]MK-801 binding but not [3H]TCP binding. The pharmacology of the high-affinity [3H]MK-801 and [3H]TCP binding sites was similar with rank order of potency of inhibitors being MK801 greater than TCP greater than phencyclidine greater than N-allylnormetazocine (SKF 10047). 2-Amino-5-phosphonopentanoate inhibited binding of both ligands with comparable potency whereas both 7-chlorokynurenic acid and ZnCl2 were more potent inhibitors of [3H]MK-801 than of [3H]TCP binding. All compounds examined exhibited Hill coefficients of significantly less than unity. Saturation analysis performed in the striatum revealed that the number of binding sites was the same for both [3H]MK-801 (Bmax, 1,403 +/- 394 fmol/mg) and [3H]TCP (Bmax, 1,292 +/- 305 fmol/mg). Addition of glutamate or glycine stimulated striatal binding but there was no further increase on addition of both together.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2003

Interaction of the novel adenosine uptake inhibitor 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride (KF24345) with the es and ei subtypes of equilibrative nucleoside transporters.

Nucleosides such as adenosine, as well as many nucleoside-based drugs, permeate cell membranes via a family of equilibrative nucleoside transporters (ENTs). We assessed the effects of (3-[1-(6,7-diethoxy-2-morpholino-quinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride (KF24345), a novel anti-inflammatory agent that potentiates the actions of adenosine, on the es (inhibitor-sensitive) and ei (inhibitor-resistant) subtypes of ENTs in human, mouse, and rat cells. KF24345 was similar to the prototypical high-affinity inhibitor nitrobenzylthioinosine (NBMPR) for blocking the human es transporter (K(I) of approximately 0.4 nM), but was 50-fold more effective than NBMPR at blocking the human ei transporter (K(I) of approximately 100 nM). KF24345 displayed significantly less species heterogeneity in its affinity for the es transporter than did dipyridamole, a widely used inhibitor of nucleoside transport; KF24345 may thus prove useful as an inhibitor for studies of nucleoside metabolism in a range of animal models. Furthermore, KF24345 seemed to act as a noncompetitive inhibitor of both [(3)H]NBMPR binding and [(3)H]nucleoside uptake by human es transporters, and these kinetics were consistent with an observed slow dissociation of KF24345 from the inhibitor binding site. KF24345 also exhibited unusual biphasic profiles for inhibition of [(3)H]NBMPR binding to membranes prepared from a recombinant human es transporter model (PK15-hENT1), suggesting the presence of multiple populations of NBMPR binding proteins in these membranes. The atypical tight binding interaction of KF24345 with the es transporter may prove useful for the molecular delineation of inhibitor binding domains and will facilitate its use as an in vivo inhibitor of nucleoside transport in studies focused on the biological effects of adenosine.

Adenosine↗
PubMed2004

Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin System.

Urotensin-II (U-II) is a cyclic peptide now described as the most potent vasoconstrictor known. U-II binds to a specific G protein-coupled receptor, formerly the orphan receptor GPR14, now renamed urotensin receptor (UT receptor), and present in mammalian species. Palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt) is a new potent and specific antagonist of the human UT receptor. ACT-058362 antagonizes the specific binding of (125)I-labeled U-II on natural and recombinant cells carrying the human UT receptor with a high affinity in the low nanomolar range and a competitive mode of antagonism, revealed only with prolonged incubation times. ACT-058362 also inhibits U-II-induced calcium mobilization and mitogen-activated protein kinase phosphorylation. The binding inhibitory potency of ACT-058362 is more than 100-fold less on the rat than on the human UT receptor, which is reflected in a pD'(2) value of 5.2 for inhibiting contraction of isolated rat aortic rings induced by U-II. In functional assays of short incubation times, ACT-058362 behaves as an apparent noncompetitive inhibitor. In vivo, intravenous ACT-058362 prevents the no-reflow phenomenon, which follows renal artery clamping in rats, without decreasing blood pressure and prevents the subsequent development of acute renal failure and the histological consequences of ischemia. In conclusion, the in vivo efficacy of the specific UT receptor antagonist ACT-058362 reveals a role of endogenous U-II in renal ischemia. As a selective renal vasodilator, ACT-058362 may be effective in other renal diseases.

Animals↗
PubMed2006

An orally active cathepsin K inhibitor, furan-2-carboxylic acid, 1-{1-[4-fluoro-2-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-oxo-piperidin-4-ylcarbamoyl}-cyclohexyl)-amide (OST-4077), inhibits osteoclast activity in vitro and bone loss in ovariectomized rats.

Human cathepsin K, a cysteine proteinase of the papain family, has been recognized as a potential drug target for the treatment of osteoporosis. The predominant expression of cathepsin K in osteoclasts has rendered the enzyme into a major target for the development of novel antiresorptive drugs. Now, we report the pharmacological properties of OST-4077 [furan-2-carboxylic acid (1-{1-[4-fluoro-2-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-oxo-piperidin-4-ylcarbamoyl}-cyclohexyl)-amide] as a novel selective cathepsin K inhibitor. Human and rat cathepsin K were inhibited in vitro by OST-4077 with the IC50 values of 11 and 427 nM, respectively. OST-4077 suppressed bone resorption induced by rabbit osteoclasts (IC50, 37 nM) but did not affect bone mineralization or cellular alkaline phosphatase activity in MC3T3-E1 cells. Parathyroid hormone-induced bone resorption was inhibited in a dose-dependent manner in thyroparathyroidectomized rats gavaged with a single dose of OST-4077 (ED50, 69 mg/kg). When given orally twice daily for 4 weeks to 3-month-old ovariectomized (OVX) rats, OST-4077 dose-dependently prevented bone loss, as monitored by bone densitometry, ash content, and urinary excretion of deoxypyridinoline. No change in serum osteocalcin in the OVX rats by OST-4077 suggested that bone formation might not be affected by the agent. In summary, OST-4077 selectively inhibited bone resorbing activities of osteoclasts and prevented bone loss induced by estrogen deficiency but did not affect bone formation. OST-4077, an orally active selective human cathepsin K inhibitor, may have the therapeutic potential for the treatment of diseases characterized by excessive bone loss including osteoporosis.

Alkaline Phosphatase↗
PubMed1996

(Alkylamino) piperidine bis(heteroaryl)piperizine analogs are potent, broad-spectrum nonnucleoside reverse transcriptase inhibitors of drug-resistant isolates of human immunodeficiency virus type 1 (HIV-1) and select for drug-resistant variants of HIV-1IIIB with reduced replication phenotypes.

The (alkylamino)piperidine bis(heteroaryl)piperizines (AAP-BHAPs) are a new class of human immunodeficiency virus type 1 (HIV-1)-specific inhibitors which were identified by targeted screening of recombinant reverse transcriptase (RT) enzymes carrying key nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-conferring mutations and NNRTI-resistant variants of HIV-1. Phenotypic profiling of the two most potent AAP-BHAPs, U-95133 and U-104489, against in vitro-selected drug-resistant HIV-1 variants carrying the NNRTI resistance-conferring mutation (Tyr->Cys) at position 181 of the HIV-1 RT revealed submicromolar 90% inhibitory concentration estimates for these compounds. Moreover, U-104489 demonstrated potent activity against BHA-P-resistant HIV-1MF harboring the Pro-236->Leu RT substitution and significantly suppressed the replication of clinical isolates of HIV-1 resistant to both delavirdine (BHAP U-90152T) and zidovudine. Biochemical and phenotypic characterization of AAP-BHAPresistant HIV-1IIIB variants revealed that high-level resistance to the AAP-BHAPs was mediated by a Gly-190->Glu substitution in RT, which had a deleterious effect on the integrity and enzymatic activity of virion-associated RT heterodimers, as well as the replication capacity of these resistant viruses.

Antiviral Agents↗
PubMed1995

PPBP [4-phenyl-1-(4-phenylbutyl) piperidine], a potent sigma-receptor ligand, decreases brain injury after transient focal ischemia in cats.

BACKGROUND AND PURPOSE: We tested the hypothesis that administration of 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), a potent sigma-receptor ligand, during transient focal ischemia would affect early postischemic brain injury. METHODS: Halothane-anesthetized cats underwent left middle cerebral artery occlusion for 90 minutes followed by 4 hours of reperfusion. Control cats received saline (n = 10). Experimental cats (2 groups, n = 10 per group) were treated with PPBP at a rate of 0.1 mumol/kg per hour (PPBP-0.1) or administered 1 mumol/kg per hour (PPBP-1) intravenously from 75 minutes after initiation of ischemia and continuing during the 4 hours of reperfusion. RESULTS: As measured by the microsphere method, blood flow to the ipsilateral caudate nucleus was decreased similarly in all groups during ischemia. Blood flow to the ipsilateral inferior temporal cortex was decreased during ischemia in all groups but was higher in cats subsequently treated with PPBP at the highest dose, even before drug administration. There was no difference in blood flow to the ipsilateral caudate nucleus or inferior temporal cortex (area of greatest cortical injury) during reperfusion. Triphenyltetrazolium-determined injury volume of the ipsilateral cerebral hemisphere (control, 29 +/- 5%; PPBP-0.1, 17 +/- 3%; PPBP-1, 6 +/- 1% of ipsilateral hemisphere; mean +/- SEM) and caudate nucleus (control, 49 +/- 5%; PPBP-0.1, 39 +/- 6%; PPBP-1, 25 +/- 5% of ipsilateral caudate nucleus) was less in cats treated with 1 mumol/kg per hour of PPBP compared with cats treated with saline. Cats treated with 0.1 mumol/kg per hour had a 45% smaller hemispheric injury volume than the control group without differences in intraischemic blood flow. Recovery of somatosensory evoked potential amplitude was greater in cats treated with PPBP-1 compared with control (control, 18 +/- 11%; PPBP-0.1, 30 +/- 14%; PPBP-1, 54 +/- 14% of baseline). CONCLUSIONS: These data indicate that sigma-receptors may play an important role in the mechanism of acute injury in both the cortex and the caudate nucleus after 90 minutes of transient focal ischemia in the cat. Because PPBP afforded protection when administered at the end of ischemia and during reperfusion, sigma-receptors may contribute to the progression of injury in ischemic border regions.

Animals↗
PubMed1996

PPBP [4-phenyl-1-(4-phenylbutyl) piperidine] decreases brain injury after transient focal ischemia in rats.

BACKGROUND AND PURPOSE: We tested the hypothesis that intravenous administration of the potent sigma-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) during transient focal ischemia would decrease postischemic brain infarction volume in rats. METHODS: Rats underwent intravascular focal ischemia for 2 hours followed by 22 hours of reperfusion. Halothane anesthesia was used only during initiation and cessation of ischemia. Rats received saline (n = 10) or 1 mumol/kg per hour PPBP (n = 10) by continuous intravenous infusion starting 1 hour after the initiation of ischemia and continuing through 22 hours of reperfusion. RESULTS: There was no difference between groups in blood pressure, arterial blood gas values, and body temperature. Triphenyltetrazolium-determined infarction volume of ipsilateral cerebral cortex (saline, 39 +/- 6%; PPBP, 21 +/- 7% of ipsilateral hemisphere; mean +/- SEM) and striatum (saline, 68 +/- 6%; PPBP, 33 +/- 8% of ipsilateral striatum) was smaller in rats treated with PPBP than in rats treated with saline. CONCLUSIONS: These data indicate that sigma-receptors may play an important role in the mechanism of injury both in cortex and striatum after 2 hours of transient focal ischemia in rats. Because PPBP afforded protection when administered at the end of ischemia and during reperfusion, sigma-receptors may influence the progression of injury in ischemic border regions.

Animals↗
PubMed2000

sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine affords neuroprotection from focal ischemia with prolonged reperfusion.

BACKGROUND AND PURPOSE: We previously showed that the intravenous administration of the potent final sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine (PPBP) provides neuroprotection against transient focal cerebral ischemia and that the protection depends on treatment duration. We tested the hypothesis that PPBP would provide neuroprotection in a model of transient focal ischemia and 7 days of reperfusion in the rat as assessed with neurobehavioral outcome and infarction volume. METHODS: Under the controlled conditions of normoxia, normocarbia, and normothermia, halothane-anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO) with the intraluminal suture occlusion technique. We used laser Doppler flowmetry to assess MCAO. At 60 minutes after the onset of ischemia, rats were randomly assigned to 1 of 4 treatment groups in a blinded fashion and received a continuous intravenous infusion of control saline or 0.1, 1, or 10 micromol. kg(-1). h(-1) PPBP for 24 hours. Neurobehavioral evaluation was performed at baseline (3 to 4 days before MCAO) and at 3 and 7 days of reperfusion. Infarction volume was assessed with triphenyltetrazolium chloride staining on day 7 of reperfusion in all rats. RESULTS: Triphenyltetrazolium chloride-determined infarction volume of ipsilateral cortex was smaller in rats treated with 10 micromol. kg(-1). h(-1) PPBP (n=15, 68+/-12 mm(3), 18+/-3% of contralateral structure, P<0.05) (mean+/-SEM) compared with corresponding rats treated with saline (n=15, 114+/-11 mm(3), 31+/-3% of contralateral structure). PPBP did not provide significant neuroprotection in the caudoputamen complex. Although MCAO was associated with several alterations in behavior, the treatment with PPBP had no effect on behavioral outcomes. CONCLUSIONS: The data demonstrate that the potent final sigma(1)-receptor ligand PPBP decreases cortical infarction volume without altering neurobehavior after transient focal ischemia and prolonged reperfusion in the rat.

Animals↗
PubMed2001

Neuroprotective effect of sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is linked to reduced neuronal nitric oxide production.

BACKGROUND AND PURPOSE: The potent final sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) provides neuroprotection in experimental stroke. We tested the hypothesis that PPBP attenuates striatal tissue damage after middle cerebral artery occlusion (MCAO) by a mechanism involving reduction of ischemia-evoked nitric oxide (NO) production. Furthermore, we determined whether the agent fails to protect ischemic brain when neuronal nitric oxide synthase (nNOS) is genetically deleted or pharmacologically inhibited (selective nNOS inhibitor, 7-nitroindazole [7-NI]). METHODS: Halothane-anesthetized adult male Wistar rats were subjected to 2 hours of MCAO by the intraluminal filament occlusion technique. All physiological variables were controlled during the ischemic insult. In vivo striatal NO production was estimated via microdialysis by quantification of local, labeled citrulline recovery after labeled arginine infusion. In a second series of experiments, nNOS null mutants (nNOSKOs) and the genetically matched wild-type (WT) strain were treated with 90 minutes of MCAO. Brains were harvested at 22 hours of reperfusion for measurement of infarction volume by triphenyltetrazolium chloride histology. RESULTS: PPBP attenuated infarction volume at 22 hours of reperfusion in cerebral cortex and striatum and markedly attenuated NO production in ischemic and nonischemic striatum during occlusion and early reperfusion. Treatment with 7-NI mimicked the effects of PPBP. In WT mice, infarction volume was robustly decreased by both PPBP and 7-NI, but the efficacy of PPBP was not altered by pharmacological nNOS inhibition in combined therapy. In contrast, PPBP did not decrease infarction volume in nNOSKO mice. CONCLUSIONS: These data suggest that the mechanism of neuroprotection of PPBP in vivo is through attenuation of nNOS activity and ischemia-evoked NO production. Neuroprotective effects of PPBP are lost when nNOS is not present or is inhibited; therefore, PPBP likely acts upstream from NO generation and its subsequent neurotoxicity.

Animals↗
PubMed1991

Fluoromethylated and hydroxymethylated derivatives of N-methyl-D-aspartate receptor antagonist 1-[1-(2-thienyl)cyclohexyl]piperidine.

Derivatives with fluoromethyl and hydroxymethyl groups on the cyclohexyl ring of 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptor, were tested in a radioligand binding assay to evaluate their ability to inhibit [3H]TCP binding by rat brain homogenates. The potencies of these compounds as antagonists of NMDA and L-glutamate responses were also compared using a rat cortical slice preparation. One of the analogs, cis-2-hydroxymethyl-r-1-(N-piperidyl)-1-(2-thienyl) cyclohexane (5) was found to show a high affinity (IC50 = 16 nM) for the phencyclidine (PCP) binding sites, very close to that of TCP, and to be 38-fold more potent in binding than its trans isomer. Fluoromethyl and hydroxymethyl substitutions at C4 position of the cyclohexyl ring of TCP clearly reduced the affinity by at least one order of magnitude relative to TCP.

Animals↗