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At least 217 records · Page 12Linked to original sources
PubMed1989

Singlet oxygen induces frank strand breaks as well as alkali- and piperidine-labile sites in supercoiled plasmid DNA.

A covalently closed, circular, supercoiled plasmid was exposed to singlet oxygen by a separated-surface sensitizer. For each exposure, the quantity of single oxygen entering the DNA target solution was estimated by its oxidation of histidine. After singlet oxygen exposure, some DNA samples were treated to disclose occult lesions. Agarose gel electrophoresis was then used to resolve the unrelaxed supercoils from the relaxed circular and linear species, and all bands were quantitated fluorometrically. Exposure of supercoiled plasmid DNA to singlet oxygen induced frank DNA strand breaks, alkali-labile sites (pH 12.5, 90 degrees C, 30 min), and piperidine-labile sites (0.4 M, 60 degrees C, 30 min), all in a dose-dependent manner. Yields of alkali-labile and piperidine-labile sites ranged from one to four times the frank strand break yield. Replacement of buffered H2O by buffered D2O as the DNA solvent for singlet oxygen exposures increased DNA lesion yields by a factor of 2.6 (averaged over lesion classes). Our data for the detection of frank strand breaks is at variance with published results from studies in which singlet oxygen was derived from a thermolabile endoperoxide dissolved in the DNA solution.

Alkalies↗
PubMed1999

Cloning and characterization of the genes encoding a cytochrome P450 (PipA) involved in piperidine and pyrrolidine utilization and its regulatory protein (PipR) in Mycobacterium smegmatis mc2155.

Transposon mutagenesis of Mycobacterium smegmatis mc2155 enabled the isolation of a mutant strain (called LGM1) altered in the regulation of piperidine and pyrrolidine utilization. The complete nucleotide sequence of the gene inactivated in mutant LGM1 was determined from the wild-type strain. This gene (pipR) encoded a member of the GntR family of bacterial regulatory proteins. An insertion element (IS1096), previously described for M. smegmatis, was detected downstream of the gene pipR. Three additional open reading frames were found downstream of IS1096. The first open reading frame (pipA) appeared to encode a protein identified as a cytochrome P450 enzyme. This gene is the first member of a new family, CYP151. By a gene replacement experiment, it was demonstrated that the cytochrome P450 pipA gene is required for piperidine and pyrrolidine utilization in M. smegmatis mc2155. Genes homologous to pipA were detected by hybridization in several, previously isolated, morpholine-degrading mycobacterial strains. A gene encoding a putative [3Fe-4S] ferredoxin (orf1) and a truncated gene encoding a putative glutamine synthetase (orf2') were found downstream of pipA.

Amino Acid Sequence↗
PubMed1990

Studies on cardiotonic agents. IV. Synthesis of novel 1-(6,7-dimethoxy-4-quinazolinyl)piperidine derivatives carrying substituted hydantoin and 2-thiohydantoin rings.

A series of novel 1-(6,7-dimethoxy-4-quinazolinyl)piperidines carrying substituted hydantoin and 2-thiohydantoin rings was synthesized and examined for cardiotonic activity in anesthetized dogs. Introduction of isopropyl and sec-butyl group at the 5-position of the hydantoin and thiohydantoin rings led to potent inotropic activity. Effects of insertion of an alkyl chain between the piperidine and the hydantoin rings were also examined. The structural requirements necessary for optimal cardiotonic activity within the series were investigated.

Animals↗
PubMed2004

Piperidine carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine as orally-active adhesion molecule inhibitors.

Novel piperidine carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine were prepared and evaluated for their inhibitory activity on the upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1). Replacement of the methanesulfonyl group on the piperidine ring of previously prepared derivatives with a carboxylic acid-containing moiety resulted in a number of potent adhesion molecule inhibitors. Of these, (anti) [3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methyl-3-azabicyclo[3.3.1]non-9-yl]acetic acid 2q (ER-49890), showed the most potent oral inhibitory activities against neutrophil migration in an interleukin-1 (IL-1) induced paw inflammation model using mice, and leukocyte accumulation in a carrageenan pleurisy model in the rat, and therapeutic effect on collagen-induced arthritis in rats.

Administration, Oral↗
PubMedDate not supplied

Acetylation and silylation of piperidine solubilized sporopollenin from pollen of Typha angustifolia L.

Silyl and acetyl derivatives of sporopollenin from the pollen of Typha angustifolia L. were prepared. The derivatized products were readily soluble in piperidine-d11 and could be investigated employing one- and two-dimensional proton and carbon NMR (nuclear magnetic resonance) spectroscopy (1H,1H-COSY and 13C,1H-HETCOR techniques). For the first time, a two dimensional 13C,1H-HETCOR NMR spectrum of a sporopollenin could be obtained. The results underline the importance of derivatization techniques for obtaining two dimensional 13C-NMR spectra of sporopollenins. Moreover, piperidine turns out to be a more suitable solvent for sporopollenins than 2-aminoethanol, as it allows for higher solubilities, being important for 2D-NMR investigations. From the HETCOR and COSY spectra of the silylated and the acetylated Typha samples the occurrence of aliphatic polyhydroxy compounds as well as phenolic OH groups became evident.

Acetylation↗
PubMed2002

Electronic-topological study of the structure-activity relationships in a series of piperidine morphinomimetics.

Structure-activity relationships (SAR) are studied in the series of 4,4-disubstituted piperidine morphinomimetics (42 compounds) by means of the Electronic-Topological Method (ETM). In the frameworks of this approach, its input data were taken as the results of conformational and quantum-mechanical calculations. These calculations had been carried out for all compounds from the series under study, taking into account their neutral and protonated by the nitrogen of piperidine cycle forms. The ETM application resulted in a set of pharmacophores and anti-pharmacophores, which formed a basis of a system used to predict analgesic activity. First of all, the system was tested on known analgesics. Testing has shown a good agreement with the experimental data. Then, the system was applied to a few compounds with similar structures but unknown activity. The results of the study could be used for computer screening and design of novel compounds with analgesics properties as new potential drugs.

Algorithms↗
PubMed1981

Metabolism of 4-benzamido-1-[4-(indol-3-yl)-4-oxobutyl]piperidine in rats and monkeys.

1. Studies on the absorption, biotransformation and excretion of the potential anti-hypertensive agent 4-benzamido-1-[4-(indol-3-yl)-4-oxobutyl]piperidine (Wy 23699) have been carried out in monkeys and rats. 2. Absorption of the drug in both species was good, as shown by the relative proportions of radioactivity found in the urine after i.v. and oral dosage. 3. Biotransformation was extensive in both species, but the major routes of metabolism were different. In monkey N-dealkylation gave rise to 4-benzamidopiperidine as the principal metabolite; two other minor metabolites were identified as 2-oxo-4-benzamidopiperidine and 4-benzamido-1-[4-(5-hydroxyindol-3-yl)-4-oxo-butyl]piperidine. In the rat, this latter compound (as its conjugate) was the major metabolite; small amounts of benzamidopiperidine but not 2-oxobenzamidopiperidine were found. 4. There was a marked species difference in the route of excretion. Monkeys excreted greater than 60% dose of the drug in the urine, while rats excreted only 19% by this route. This may reflect the species difference in routes of metabolism, metabolic scission of the drug molecule seen in the monkey favouring renal rather than biliary excretion. The toxicological consequences of this are discussed.

Animals↗
PubMed1999

Degradation of morpholine, piperidine, and pyrrolidine by mycobacteria: evidences for the involvement of a cytochrome P450.

Nine bacterial strains that grew on morpholine and pyrrolidine as sole carbon, nitrogen, and energy sources were isolated from three different environments with no known morpholine contamination. One of these strains could also degrade piperidine. These bacteria were identified as Mycobacterium strains. A phylogenetic analysis based on the partial 16S rDNA sequences indicated that the isolated strains clustered within the fast growing group of mycobacteria. When the above-mentioned cyclic amines were used as growth substrates, the synthesis of a soluble cytochrome P450 was induced in all these bacteria. Other laboratory strains, Mycobacterium fortuitum and Mycobacterium smegmatis mc(2)155, were tested for their abilities to degrade morpholine. Neither of them degraded morpholine but could use pyrrolidine and piperidine. The growth of M. fortuitum and M. smegmatis mc(2)155 on these compounds involved a soluble cytochrome P450, suggesting that mycobacterial strains are naturally able to use pyrrolidine and have developed a similar enzymatic pathway to metabolize this amine.

Base Sequence↗
PubMed2000

Synthesis and evaluation of 4-(N,N-diarylamino)piperidines with high selectivity to the delta-opioid receptor: a combined 3D-QSAR and ligand docking study.

A series of 4-(N,N-diarylamino)piperidines are synthesized and evaluated for high affinity binding and selectivity to the delta-opioid receptor using a combination of 3D-QSAR and molecular docking techniques. Based on experimental ligand binding data to both mu- and delta- opioid receptors, CoMFA fields are generated and applied to identify potential ligand modifications to further optimize lead compounds. Molecular docking experiments to the delta-receptor are also reported that explain the CoMFA trends predicted as well as the differential binding and selectivity displayed by various compounds in the series. An analysis of the binding site model proposed indicates the piperidines take advantage of 3 key sites or binding domains within the delta-receptor. These include an aromatic pocket (approximately 1/3 into the receptor cavity), an aspartic acid residue (which serves as a docking point for the piperidinyl cationic amine) and a hydrophobic pocket at the extracellular boundary of the receptor cavity. Links are established between ligand modification and amino acid composition at these sites in mu and delta, providing new insight to the structural basis to binding and selectivity across the series and for related piperazines (i.e. SNC80 and BW373U86). Results are also presented that indicate delta- and mu-selectivity may be determined at alternate sites, suggesting opioid receptors may display multiple binding domains. The model is further supported by comparisons with opiate binding modes and site directed mutagenesis studies and is finally applied to suggest new strategies in ligand design.

Amino Acid Sequence↗
PubMed1975

Biochemical pharmacology of some chlorinated 3-phenyl-piperidines in rats.

Chlorinated 3-phenyl-piperidines were administered to rats with the expectation--based on structural similarities--that they might resemble chlorinated amphetamines pharmacologically. The 3-chloro, 4-chloro, and 3,4-dichloro compounds all lowered serotonin and 5-hydroxyindoleacetic acid levels in rat brain, whereas the 2-chloro compound had no effect. The brain levels and half-lives of the four compounds suggested that the compounds might be metabolized by hydroxylation at the 4- position of the phenyl ring. Desmethylimipramine, an inhibitor of amphetamine hydroxylation in the 4- position, markedly elevated brain levels of the 2-chloro compound and to a lesser extent of the 3-chloro compound. The 2-chloro compound did not lower brain serotonin levels even in desmethylimipramine-treated rats, however. The results suggest that some pharmacologic properties of the chlorinated 3-phenyl-piperidines are indeed similar to those of chlorinated amphetamines.

Amphetamine↗
PubMedDate not supplied

Synthesis and pharmacological properties of new pyridine derivatives.2,6-bis-[diphenyl-(and dibenzyl)-hydroxymethyl]-piperidines.

Syntheses of 2,6-bis-(diphenylhydroxymethyl)-, 2,6-bis-(dibenzylhydroxymethyl)- and 2,6-bis-(phenylbenzylhydroxymethyl)-pyridines were carried out. These compound were hydrogenated to the corresponding piperidine carbinols. The compounds are of low toxicity and were tested on mice for their CNS activity, using climbing test. 2,6-bis-(dibenzylhydroxymethyl)-piperidine (VI) exhibited central depressive activity.

Animals↗
PubMed1992

DuP 734 [1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'-oxoethyl)- piperidine HBr], a sigma and 5-hydroxytryptamine2 receptor antagonist: receptor-binding, electrophysiological and neuropharmacological profiles.

It has been suggested that sigma receptor antagonists may be useful as antipsychotic drugs and that 5-hydroxytryptamine (5-HT2) receptor antagonists produce improvements of the negative symptoms of schizophrenia. [1-(Cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'- oxoethyl)-piperidine HBr] (DuP 734) is a novel compound with high affinity for the sigma (Ki = 10 nM) and 5-HT2 (Ki = 15 nM) receptors, but low affinity for dopamine receptors (Ki > 1000 nM) as well as 33 other receptors, ion channels and second messenger systems in vitro. DuP 734 did not inhibit the synaptosomal uptake of dopamine, 5-HT or norepinephrine. Oral administration of DuP 734 potently blocked 5-hydroxy-L-trytophan (5-HTP)-induced head twitch in the rat (ED50 = 6.5 mumol/kg), indicating 5-HT2 antagonist activity. Extracellular single-unit recording studies demonstrated that DuP 734 antagonized the effect of the selective sigma ligand (+)-3-(3-hydroxyphenyl-N-(1-propyl) piperidine [(+)-3-PPP] on dopamine neuronal activity in the substantia nigra of the rat with an ED90 of 3.6 mumol/kg i.v. The sigma receptor agonists (+)-SKF 10,047 and phencyclidine both elicited rotational behavior in rats with unilateral lesion of the substantia nigra. The rotational behavior induced by either (+)-SKF 10,047 or phencyclidine was dose-dependently antagonized by DuP 734 with oral ED50 of 8.7 and 19.6 mumol/kg, respectively. The 5-HT2 receptor antagonist ICI 169,369, even at high doses (up to 33 mumol/kg, s.c.), did not antagonize the rotational behavior induced by (+)-SKF 10,047.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Structure-activity studies of morphine fragments. I. 4-alkyl-4-(m-hydroxy-phenyl)-piperidines.

The 4-(m-OH-phenyl)piperidines are a flexible fragment of the morphine/benzomorphan fused-ring opioids. Analogs in this family were synthesized with varying 4-alkyl substituents increasing in bulk from H through methyl, n-propyl, to t-butyl, each with the three N-substituents methyl, allyl, and phenethyl. These twelve compounds were evaluated for analgetic agonism in mice using two different models for antinociceptive activity, acetic acid writhing and tail-flick, the latter by both subcutaneous and intracerebroventricular routes of administration. Antagonism to morphine analgesia was also measured by the mouse tail-flick procedure. Binding affinities of these new analogs to different opioid receptor subtypes were determined. Energy conformational calculations on these compounds were also carried out using the empirical energy program called MOLMEC, in order to better understand how the 4-R substituents modulate receptor binding affinities and efficacies. The results obtained show that, in general, the compounds studied are mu-selective and vary in agonist potency from weak to morphine-like. Significant differences in rank order of analgetic potencies and their relationship to receptor affinities were obtained from the results of subcutaneous and intracerebroventricular administration. Results of energy-conformational calculations for twelve N-methyl compounds indicate that those with 4-alkyl substituents favor a common, non-morphine-like phenyl axial conformation. The 4-t-butyl compounds are, in fact, the first simple mono-alkyl-substituted 4-phenyl-piperidines predicted to definitely exist in a phenyl axial conformation, as confirmed by X-ray analysis. On the basis of this common phenyl axial conformation, the observed variation in mu receptor affinities and efficacies of the 4-methyl, 4-n-propyl, and 4-t-butyl compounds could be understood and the behavior of 4-ethyl and 4-isopropyl analogs predicted. Two equatorial conformers (rotamers) were found to be the preferred forms of the analogs with 4-R being H or an ester group, or with a 3-methyl group added trans (beta) to the 4-R group. Taking into account the rotational flexibility of these analogs, these two conformers could be used to understand differences in high and low efficacy compounds observed among analogs with preferred phenyl equatorial conformations. None of the analogs exhibit a fused-ring-like N-substituent modulation of efficacy. This result can, perhaps, be understood by their inability in any proposed conformer to totally mimic key receptor interactions of both the phenol-OH and N-substituent portions of the fused compounds.

Analgesics↗
PubMedDate not supplied

[Specific interaction of piperidine derivatives with human serum albumin].

When the series of 4-substituted derivatives of 2,2,6,6-tetramethyl piperidine-I-oxide (TMPO) interacts with human serum albumin (HSA) in 0.01 M Na-acetate buffer, pH 5.6 in differential spectra there appears the intensive maximum at 232-235 nm characteristic of protein denaturation. It is suggested that specifics of nitroxyl binding with HSA is mainly determined by the conformational state of TMPO (twist or chair), since corresponding 4-nitro piperidines having other conformation result in the appearance of the band at 232.5 nm with a much lower intensity. It is recommended to take into account possible significant structural changes of albumins when studied by the spin label method using TMPO or its derivatives.

Humans↗
PubMed1996

4-(1-Naphthylamino)-piperidines as inhibitors of lipid peroxidation.

Some analogues of (+/-)-N-methyl-N-¿1-[3-(4-fluorophenoxy)-2-hydroxy-propyl]-piperidin+ ++-4-yl¿ benzothiazol-2-amine (sabeluzole, CAS 104383-17-7), a series of 4-(l-naphthylamino)-piperidines (1a-1h), are potent inhibitors of both NADPH- and Fe(2+)-dependent lipid peroxidation (IC50 < 10 mumol/1). It was demonstrated that the naphthylaminopiperidine moiety is responsible for this effect due to its antioxidant property, verified by cyclic voltammetric studies.

Animals↗
PubMed1998

Teratogenic and fetotoxic effects of two piperidine alkaloid-containing lupines (L. formosus and L. arbustus) in cows.

Cleft palate and minor front limb contractures were induced in calves by maternal ingestion of the piperidine alkaloid-containing lupines, Lupinus formosus and L. arbustus. Crooked calf disease, which includes an occasional cleft palate, is a congenital condition of widespread occurrence in cattle in the western U.S. and Canada. It is known to occur after maternal ingestion of certain species of Lupinus during specific gestational periods. Although many lupine species contain quinolizidine alkaloids including the teratogenic alkaloid anagyrine, L. formosus and L. arbustus produce piperidine alkaloids including the reported teratogen ammodendrine. In addition to ammodendrine, L. formosus contains both N-acetyl hystrine and N-methyl ammodendrine, whereas L. arbustus contains ammodendrine, trace amounts of N-methyl ammodendrine, and no N-acetyl hystrine. L. formosus and L. arbustus were fed to pregnant cows at equivalent ammodendrine doses during a 10-day period from days 40-50 of gestation. One calf from a cow fed L. formosus had a full cleft palate. Embryonic death and resorption of one fetus and minor front limb contractures (arthrogryposis) in another calf occurred with two cows fed L. arbustus. Alkaloid analysis of blood samples taken during the feeding period, and up to and including 48 hours after the last dose, demonstrated comparative plasma elimination times with N-methyl ammodendrine > ammodendrine > N-acetyl hystrine. The objectives of this experiment were to: 1) determine if N-acetyl hystrine is a potential teratogen; and 2) define the narrow cleft palate induction period in cows.

Alkaloids↗
PubMed2006

Chiral oxazolopiperidone lactams: versatile intermediates for the enantioselective synthesis of piperidine-containing natural products.

Phenylglycinol-derived oxazolopiperidone lactams are exceptionally versatile building blocks for the enantioselective construction of structurally diverse piperidine-containing natural products and bioactive compounds. These lactams are readily available in both enantiomeric series by cyclocondensation of the chiral amino alcohol with a delta-oxo acid derivative and allow the substituents to be introduced at the different ring positions in a regio- and stereocontrolled manner, providing access to enantiopure polysubstituted piperidines bearing virtually any type of substitution pattern, and also quinolizidines, indolizidines, perhydroquinolines, hydroisoquinolines, as well as complex indole alkaloids. Of particular interest are cyclocondensation reactions with racemic or prochiral delta-oxo (di)acid derivatives in processes involving dynamic kinetic resolution and/or differentiation of enantiotopic or diastereotopic ester groups, as they directly lead to lactams that already incorporate the carbon substituents on the heterocyclic ring. The use of (S)-3,4-dimethoxyphenylalaninol or (S)-tryptophanol in the above cyclocondensation reactions expands the potential and the scope of the methodology, providing a straightforward route to enantiopure benzo[a]- and indolo[2,3-a]quinolizidines.

Alkaloids↗