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PubMed1990

Multiple vascular effects of sigma and PCP ligands: inhibition of amine uptake and contractile responses.

The functional effects of sigma and PCP receptor ligands were examined in the perfused rat tail artery. The following ligands were studied: haloperidol; (+)-3-PPP [(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine]; (+-)-BMY 14802 [(+-)-alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol]; DTG [1,3-di-orthotolyl-guanidine]; rimcazole (BW 234U) [cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride]; (+)-SKF 10047 [(+)-N-allyl-N-normetazocine]; TCP, [1-[1-(2-thienyl)cyclohexyl] piperidine]; and MK 801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate]. (+)-3-PPP, (+)-SKF 10047, MK 801 and TCP potentiated contractile responses to norepinephrine, an effect which was blocked by cocaine implying an action of these agents on monoamine uptake. In the presence of cocaine an additional postjunctional inhibitory action of (+)-3-PPP and (+)SKF 10047 on norepinephrine-induced contractile responses was unveiled. In contrast, haloperidol, (+/-)-BMY 14802, rimcazole and DTG inhibited contractile responses to norepinephrine. Haloperidol, (+/-)-BMY 14802 and (+)-SKF 10047 (+ uptake blockade) also inhibited contractile responses to serotonin. The order of potency for inhibition of norepinephrine-induced contractions was haloperidol greater than (+/-)-BMY 14802 greater than (+)-3-PPP greater than rimcazole greater than (+)-SKF 10047 (+ uptake blockade) greater than DTG. These studies demonstrate the lack of selectivity of many sigma and PCP ligands, significant effects on norepinephrine uptake, as well as the potential utility of the rat tail artery to explore the functional properties of these ligands.

Animals↗
PubMed1989

[Studies on the metabolism of antiepilepserine in isolated perfused rat liver].

The metabolism of antiepilepserine, 3,4-methylene dioxycinnamyl piperidine, was studied in isolated perfused rat liver. Two metabolites were separated and purified by means of HPLC. They were identified as 3,4-methylene dioxycinnamyl hydroxypiperidine and 4-hydroxy-3-methoxycinnamyl piperidine by UV and MS. The latter was further confirmed by chemical synthesis. The pharmacokinetics of antiepilepserine in isolated perfused liver was also studied. Parameters obtained include a first order elimination constant, k = 0.0157 +/- 0.0043 min-1, and a half-life, t 1/2 = 46.7 +/- 11.9 min, (n = 6). The amount of antiepilepserine lost during the perfusion could not be compensated by the increased amount of metabolites. Antiepilepserine was found to be tightly bound and stored in the liver. This might be one of the explanations of the first pass effect of antiepilepserine after oral administration.

Animals↗
PubMed1988

4,4-Diphenylpiperidine derivates and their sila analogues. A comparative study of their interaction with neural receptor biding sites and synaptosomal monoamine uptake.

The potential anti-Parkinson drugs 1-R-4,4-diphenylpiperidines and 1-R-4,4-diphenyl-4-sila-piperidines (R = H, CH3, i-propyl and t-butyl) were evaluated for their neuroreceptor affinity with respect to their structure-activity relationship. In these compounds substitution of the central carbon at position 4 by a silicon leads to more lipophilic substances. While the binding of these compounds to dopamine, serotonin and gamma-aminobutyric acid/benzodiazepine receptors is relatively non-specific, the binding to the mu- and delta-subtypes of opiate receptors and to the 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine receptor binding site show probably pharmacologically relevant effects. In almost all cases the sila-compounds have a slightly higher receptor affinity than the corresponding carbon-compounds. The studies on the uptake sites for the biogenic amines noradrenaline, dopamine and serotonin, on the other hand, reveal some considerable differences between the carbon- and silicon-containing analogues. The 4,4-diphenyl-4-sila-piperidine has much stronger uptake inhibiting properties for noradrenaline and serotonin than the corresponding carbon compound.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents. I. Evidence for efficacy in models of focal cerebral ischemia.

Recent studies have strongly implicated the excitatory neurotransmitter glutamate in the cascade of pathological mechanisms that cause neuronal loss after certain types of brain ischemia. The neurotoxic effects of glutamate are mediated, at least in global ischemia, via NMDA receptors. In the present study we have examined the effects of compounds that possess NMDA receptor antagonist properties (ifenprodil, SL 82.0715 [(+/-)-alpha-(4-chlorophenyl)-4-[(4-fluorophenyl)methyl]- 1-piperidineethanol] and 1-[1-(2-thienyl)cyclohexyl]piperidine) on the histological consequences of focal, as opposed to global, cerebral ischemia in both the rat and the cat. Ifenprodil (0.3-3 mg/kg i.v.) administered as a perfusion over 3 hr after occlusion of the feline middle cerebral artery reduced the volume of infarcted tissue (measured 4 days after occlusion) in a dose-related manner. At the highest dose a 42% reduction of infarcted volume was noted, essentially in cortical tissue. In an identical protocol, a derivative of ifenprodil, SL 82.0715, reduced the volume of infarction in a manner comparable to that described for ifenprodil. As SL 82.0715 possesses better p.o. bioavailability, this compound was also evaluated in the rat, again after middle cerebral artery occlusion. First administered 30 min after the induction of ischemia, SL 82.0715 (1 and 10 mg/kg p.o.) reduced infarction volume by 34 and 48%, respectively. The quantitative histology was performed 2 days after middle cerebral artery occlusion. The noncompetitive receptor antagonist, 1-[1-(2-thienyl)cyclohexyl]piperidine, administered (1 mg/kg i.p.) before the induction of focal ischemia, similarly and significantly decreased the final volume of infarction. As both ifenprodil and SL 82.0715 are noncompetitive antagonists of the NMDA receptor, two conclusions may be drawn from the present investigation. First, NMDA antagonism by ifenprodil and its derivative is an effective approach for tissue sparing in animal models of stroke and brain infarction. Second, these pharmacological observations provide evidence for the involvement of excitatory amino-acid induced-neurotoxicity in the evolution and consequences of focal cerebral ischemia.

Animals↗
PubMed1987

Synthesis and biological activity of a GABAA agonist which has no effect on benzodiazepine binding and of structurally related glycine antagonists.

3-Isoxazolols substituted in the 5-position by pyrrolidinyl or piperidyl (referred to, respectively, as PYOLs and PIOLs; see Figure 2 for structures) were designed and synthesized as analogues of the potent and specific GABAA agonist THIP. Activity in the series was markedly dependent upon positional isomerism in the structures. Isomers in which the pyrrolidine or piperidine rings were attached via their 2-positions (2-PYOL and 2-PIOL) had no effect on GABAA receptors in vivo or in vitro. An isomer wherein attachment was via the 4-position (4-PIOL) was a GABAA agonist, but it was unique in not affecting the binding of diazepam in vitro; its 'ring-opened' analogue, (RS)-5-(1-methyl-3-aminopropyl)-3-isoxazolol (11) did not bind significantly to GABAA receptor sites in vitro. In contrast, the 3-positional isomer (3-PIOL) antagonized the inhibitory action of glycine on cat spinal neurons. A similar effect was earlier demonstrated for 3-PYOL. However, in contrast to 3-PYOL, which is approximately equipotent as an antagonist of glycine and GABA, 3-PIOL only marginally reduced the inhibitory effect of GABA. The R and S forms of 3-PIOL, synthesized from the respective isomers of piperidine-3-carboxylic acid with known absolute stereochemistry, had pharmacological profiles indistinguishable from that of racemic 3-PIOL.

Animals↗
PubMedDate not supplied

Excretion and biotransformation of cisapride in dogs and humans after oral administration.

The excretion and biotransformation of cisapride, a novel gastrokinetic drug, were studied after a single po dose of [14C]cisapride in dogs and humans. The excretion of radioactivity amounted to 97% within 4 days after a 1 mg/kg dose in dogs (72% in feces and 25% in urine). After a 10-mg dose in humans, 44% was excreted in the 0-24-hr urine and 37% in the 0-35-hr feces; excretion was complete within 4 days. Excretion of the parent drug was greater in dogs (0.4-1.3% of the dose in urine, 23% in feces) than in humans (0.2% in urine, 4-6% in feces). This was due, at least in part, to a larger proportion of amine glucuronidation and sulfation in dogs. N-Deal-kylation at the piperidine nitrogen resulting in the main urinary metabolite, norcisapride, and aromatic hydroxylation of the 4-fluorophenyl ring were major metabolic pathways in both species. Norcisapride excretion accounted for 14% of the dose in dogs and 41-45% in humans. Minor metabolic pathways were O-dealkylation at the 4-fluorophenoxy group and piperidine oxidation. Peak plasma levels and AUC values of norcisapride in humans were 8-9 times lower than those of cisapride. Apart from more amine conjugation in dogs, the biotransformation of cisapride was similar in dogs and humans.

Administration, Oral↗
PubMedDate not supplied

Excretion and biotransformation of cisapride in rats after oral administration.

The excretion and biotransformation of cisapride, a novel gastrokinetic drug, were studied after single (10, 40, and 160 mg/kg) and repeated (10 mg/kg/day) po administration to rats, using three different radiolabels. In fasted rats, cisapride was absorbed almost completely, except for the 160 mg/kg dose. Cisapride was metabolized extensively to at least 30 metabolites. The excretion of the metabolites amounted to more than 80% of the dose at 24 hr and was almost complete at 96 hr after dosing. In bile duct-cannulated rats, 60% was excreted in the bile within 24 hr, 45% of which underwent enterohepatic circulation. The main urinary metabolites, 4-fluorophenyl sulfate and norcisapride, primarily resulted from the N-dealkylation at the piperidine. Another major metabolic pathway was aromatic hydroxylation, occurring on either the 4-fluorophenoxy or the benzamide rings. The resulting phenolic metabolites were eliminated as conjugates in the bile; a large portion of them were subjected to a rapid enterohepatic circulation before their final excretion in the feces. Minor metabolic pathways included piperidine oxidation, O-dealkylation, O-demethylation of the methoxy substituent at the benzamide, and amine glucuronidation. Only minor quantitative dose- and sex-dependent differences could be observed for the mass balance of the metabolites. Upon repeated po dosing, steady state excretion rates were already attained after two to three doses, and excretion and metabolite patterns were very similar to those after single dose administration.

Administration, Oral↗
PubMed1979

Evidence for a noncholinergic site for nicotine's action in brain: psychopharmacological, electrophysiological and receptor binding studies.

In an effort to investigate the possibility of noncholinergic nicotine sites within the brain, psychopharmacological, biochemical and eletrophysiological studies were undertaken with nicotine and various newly synthesized derivatives of nicotine and piperidine. When 1-10 micrograms of (-)-nicotine was injected into the region of the lateral ventricle of rats through implanted cannulae, there resulted a characteristic prostration immobilization syndrome, which was accompanied by seizures and tremors at the higher dose range. The (+)-isomer possessed 1/100 the activity of the natural (-)-isomer. The syndrome could be prevented by pre-treatment, intraventricularly, with the N-benzyl and N-p-nitrophenylazido derivates of either nicotine or piperide. A variety of neurotransmitters and psychotropic agents, including acetylcholine and anticholinergic drugs, were without antagonistic action. After nicotine, recordings of spontaneous electrical activity from electrodes chronically implanted into the region of the dorsal hippocampus showed a marked decrease in the amplitude and number of 6-8 sec discharges, and the change was correlated with the behavioral syndrome. Receptor binding studies were performed with rat brain slices and various neural preparations using 3H-nicotine, 125I-alpha-bungarotoxin and 14C-d-tubocurarine as ligands; and only with 3H-nicotine was it possible to demostrate any competitive effect with the various nicotine and piperidine antagonists. It was possible to demonstrate stereospecific or specific nicotine binding to only glass fiber filters and, to a lesser extent, brain slices, but not to cell-free preparations. It was concluded that there existed specific noncholinergic sites for nicotine's action which have not been hitherto described.

Animals↗
PubMedDate not supplied

Excretion and biotransformation of ketanserin after oral and intravenous administration in rats and dogs.

The excretion and biotransformation of ketanserin, a novel serotonin S2-receptor blocking agent used in hypertension and related diseases, were studied after single po (1 or 10 mg/kg) and iv (2.5 mg/kg) administration in rats and dogs, using two different radiolabels. Orally administered ketanserin was well absorbed and almost completely metabolized in both species. The excretion of the metabolites was rapid and amounted to about 90% within 4 days. In the various groups of rats and dogs, excretion of the radioactivity with the feces (48 to 67%) exceeded that with urine (27 to 43%). In po dosed bile-cannulated rats, 57% was excreted with the bile within 24 hr, whereas about 30 to 40% of the biliary radioactivity was subjected to enterohepatic circulation. The major urinary, biliary, and fecal metabolites were characterized by HPLC and mass spectrometric analysis. The main metabolic pathways of ketanserin were the aromatic hydroxylation at the quinazolinedione moiety, the oxidative N-dealkylation at the piperidine nitrogen, reduction of the ketone function and piperidine oxidation, followed by ring scission. The mass balance of the metabolites, as estimated by reversed-phase HPLC with on-line radioactivity detection, was very similar between male and female rats, as well as between rats po dosed at 10 mg/kg and iv dosed at 2.5 mg/kg. In rats, major urinary metabolites resulted from the N-dealkylation pathway, whereas hydroxyketanserin was the main biliary and fecal metabolite. In dogs, the N-dealkylation pathway was less abundant, whereas higher doses resulted in smaller relative amounts of hydroxylated metabolites and larger relative amounts of ketanserin-ol, resulting from the ketone reduction. Dog plasma levels of ketanserin-ol exceeded those of the parent drug from about 5 hr after po dosing.

Administration, Oral↗
PubMed1984

[Synthesis, physical-chemical properties and pharmacologically-oriented screening studies on budipine and related 4,4-diphenylpiperidines].

1-Alkyl-4,4-diphenylpiperidines 5-23 are accessible in a simple manner and with attractive yields by regioselective reaction of piperidine derivatives like 1, 2, 3 or particularly 3-aroyl-4-aryl-4-hydroxypiperidines 4, which can be varied widely at the nitrogen atom, with benzene under Friedel-Crafts conditions. The physico-chemical parameters, which are important for the transport and the distribution of a drug in a living system, are discussed for the 1-tert-butyl derivative 13 (budipine) (pKa, partition coefficient P, saturation concentration Cs, surface activity, protein binding). Rapid absorption of this drug in man is indicated by the size of the permeability coefficient PM of the passive transport through artificial phospholipid collodium membranes as well as the invasion curves calculated from PM. According to pharmacological screening tests, most of the compounds of this class show marked antagonistic activity against experimentally generated pathological states in mice (tremorine and reserpine antagonism) which suggest their potential use in the therapy of Parkinson's disease. 13 has been selected for detailed investigations. Structure-activity analyses did not readily demonstrate the presence of a relationship between the type of alkyl substituent at the piperidine nitrogen atom and the pharmacological screening results obtained.

Animals↗
PubMedDate not supplied

[Ornithine decarboxylase activity in malignant tumors].

Activity of ornithine decarboxylase was studied in transplantable hepatomas G-27, G-22, G-61, G-60, G-48, G-46, in liver tissues of tumor-bearing and intact animals as well as in liver tissue during hepatocarcinogenesis and after repeated administration of nitrose piperidine. The rate of ornithine decarboxylation was distinctly increased in hepatomas G-27, G-60, G-46 and G-48 as compared with liver tissue of tumor-bearing and intact animals. The enzymatic activity in hepatomas G-22 and G-61 was similar to the activity found in liver tissue of intact animals. In liver tissue of tumor-bearing animals the enzyme activity was significantly increased only in hepatoma 22. Repeated administration of nitrose piperidine did not affect the ornithine decarboxylase activity in rat liver tissue. The carcinogenesis, caused by nitrosamine effect, increased distinctly the enzymatic activity in rat liver tissue up to the moment of the primary hepatomas development.

Animals↗
PubMed1993

Opiate receptors within the blood-brain barrier mediate kappa agonist-induced water diuresis.

Data suggest that kappa opioid agonist-induced water diuresis involves inhibition of vasopressin (AVP) secretion; however, it is not clear whether this action involves kappa receptors in the neurohypophysis or receptors behind the blood-brain barrier (BBB). We have investigated the site of action using three selective kappa agonists, BRL 52656 (S(-)-2-(1-pyrrolidinylmethyl)-1-(4-trifluoromethylphenyl) acetyl piperidine hydrochloride), BRL 53114 ((-)-1-(4-trifluoromethylphenyl) acetyl-2-(1-pyrrolidinymethyl)3,3- dimethyl piperidine hydrochloride) and BRL 52974 (4-(1-pyrrolidinylmethyl)5-(3,4-dichlorophenyl)acetyl-4,5,6,7-t etrahydroimidazo [4,5-c] pyridine), with varying abilities to cross the BBB. Chemical and functional assays indicate that BRL 52974 has limited ability to cross the BBB, whereas BRL 53114 and BRL 52656 can freely penetrate. BRL 52974 was significantly less potent than BRL 52656 and BRL 53114 in causing a water diuresis in conscious rats. The ED10S (i.v. doses to cause a positive free water clearance of 10 microliters/min.100 g) for BRL 52974, BRL 52656 and BRL 53114 were 181, 9 and 3.4 mg/kg, respectively. Furthermore, in dogs BRL 52656 and BRL 53114 but not BRL 52974 (30 micrograms/kg i.v.) were able to cause a significant water diuresis. The data demonstrate that opiate receptors behind the BBB are primarily involved in kappa agonist-induced water diuresis and possibly inhibition of AVP secretion.

Animals↗
PubMed1993

Autoradiographic mapping of M3 muscarinic receptors in the rat brain.

The regional distribution of putative M3 receptors was studied by quantitative autoradiography of rat brain sections labeled with 4-diphenylacetoxy-N-methyl-piperidine methioxide. The radioligand appears to label multiple muscarinic receptor subtypes in direct binding assays, as evidenced by competition experiments with unlabeled pirenzepine and 11-([2-[(2-(diethylamino)methyl]-1- piperidinyl]acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodi azepine-6-on. Conditions favoring the selective labeling of M3 receptors were determined on the basis of the competition studies and were subsequently applied to regional mapping of M3 receptor binding. Under the conditions used, autoradiographic images may be obtained with both 9-fold M3-to-M1 selectivity and 12-fold M3-to-M2 selectivity. Although distributed widely at relatively low prevalence throughout the neuraxis, M3 receptors are apparently enriched relative to M1 and M2 receptors in several diencephalic and brain stem regions including thalamic and hypothalamic nuclei, the substantia nigra, superior colliculus, periaqueductal gray and the pons. The present results suggest that the binding of 4-diphenylacetoxy-N-methyl-piperidine methioxide, under appropriate conditions, may permit direct estimation of M3 receptors in mammalian brain.

Animals↗
PubMedDate not supplied

Preparation and pharmacological activities of spiro[3,4-dihydro-6/7-R-1,2,4-benzotriazine-3,4'-(1'-substituted)piperi dines].

A set of spiro[3,4-dihydro-1,2,4-benzotriazines-3,4'-piperidine] derivatives was prepared and subjected to a broad pharmacological screening. Many of these compounds are characterized by a 3-(4-fluorobenzoyl)propyl substituent on the piperidine nitrogen, thus resembling the p-fluorobutyrophenone antipsychotics. Modest dopamine antagonism was observed for the tested compounds, which however were mainly endowed with analgesic and antihypertensive activities. Antihypercholesterolemic activity was also seen in compound 5, which represents an interesting new lead, being completely structurally unrelated to the known agents in this field.

Analgesics↗
PubMedDate not supplied

[Quenching of triplet states by Fe(II)- and Fe(III)-porphyrins].

The quenching of triplet states of metalloporphyrin molecules differing in the position of the lowest triplet state (from 9.000 to 15.000 cm-1) by ion complexes of octaethylporphin (OEP) has been investigated. High-spin ferric complex FeCl-OEP in dimethylformamide, toluene and ethanol, low-spin ferric complex FeCl(imidazole)2-OEP in toluene and diamagnetic ferrous complex Fe(piperidine)2-OEP in pyridine-piperidine (25:1) were used as quenchers. It has been found that all iron complexes investigated are effective quenchers of triplet states. The values of bimolecular quenching constants fall within the limits of (1 divided by 4) X 10(9) M-1 sec-1. Energy transfer to low-lying excited levels of iron porphyrins which are due to the presence of 3d electrons of ferric (ferrous) ion has been shown to play an essential role in the quenching process.

Chemical Phenomena↗
PubMed1982

Hyperpipecolic acidemia. Occurrence in an infant with clinical findings of the cerebrohepatorenal (Zellweger) syndrome.

An infant with clinical presentation of the cerebrohepatorenal syndrome (CHRS) of Zellweger was found to have increased plasma and urinary concentrations of pipecolic acid. When given a loading dose of DL-pipecolic acid hydrochloride, she showed a reduced clearance rate for that acid. Piperidine, delta 6-piperidine-2-carboxylic acid, and alpha-aminoadipic acid were not detected in plasma or urine. Her response to a lysine load was comparable to that of controls. These data provide further evidence of the connection between hyperpipecolic acidemia and CHRS.

2-Aminoadipic Acid↗
PubMed2006

Synthesis and biological evaluation of new quinazoline and cinnoline derivatives as potential atypical antipsychotics.

Four new diaza analogues (14, 15, 23, and 24) of the conformationally constrained aminobutyrophenone derivatives QF0104B (5) and QF0108B (6) were synthesized (Schemes 2 and 3), and evaluated for their binding affinities (Table) towards the serotonin 5-HT2A and 5-HT2C, and the dopamine D2 receptors. Among the new compounds, the quinazoline derivative 15 (= 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydroquinazolin-5-one) exhibited the highest affinities towards the serotonin 5-HT2A and dopamine D2 receptors, and it is in the borderline of potential atypical antipsychotics. The cinnoline derivative 23 (= 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydro-3-methylcinnolin-5-one) displayed high selectivity in its binding profile towards the 5-HT2C compared to both the 5-HT2A and D2 receptors.

Antipsychotic Agents↗
PubMed1992

Enantiospecificity of kappa receptors: comparison of racemic compounds and active enantiomers in two novel series of kappa agonist analgesics.

Two novel series, Ia,b and IIa,b, of kappa opioid antinociceptive agents have recently been described. 2a,b,3a,b,c The biological activities of 16 racemic compounds and their corresponding (-) enantiomers are now compared in a battery of tests. Enantiomers of unsubstituted piperidines Ia were synthesized starting from S(-) pipecolic acid, whereas the enantiomerically pure substituted piperidines (Ib), tetrahydroisoquinolines (IIa), and thienopiperidines (IIb) were, in general, obtained after diastereomeric crystallization of the corresponding tartrate salts. The absolute stereochemistry of one representative enantiomer from series IIa was determined to be (1S) by X-ray crystallographic analysis. Antinociceptive activity in the mouse abdominal constriction and tail-flick tests following subcutaneous administration, and binding affinity for kappa and mu receptors, were found to reside predominantly in the (-) enantiomers. Consequently, racemic compounds showed approximately half potency of the corresponding enantiomers. This potency difference was less clear after oral administration presumably due to small differences in bioavailability of the two corresponding enantiomers. For compounds with some affinity also for mu receptors (Ki less than 1,000 nM), the kappa/mu selectivity was maintained within each enantiomeric pair, in contrast to results found for other kappa agonists.

Analgesics↗