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PubMed2000

Sequence specificity of alkali-labile DNA damage photosensitized by suprofen.

On irradiation at UVB wavelengths, in aerated neutral aqueous solution, the anti-inflammatory drug suprofen (SP) photosensitizes the production of alkali-labile cleavage sites in DNA much more efficiently than direct strand breaks. It is active at submillimolar concentrations despite having no significant binding affinity for DNA. Gel sequencing studies utilizing 32P-end-labeled oligonucleotides have revealed that piperidine-sensitive lesions are formed predominantly at the positions of guanine (G) bases, with the extent of modification being UV dose- and SP concentration-dependent. Quite distinct patterns of G-specific damage are observed in single-stranded and duplex DNA molecules. The uniform attack at all G residues in single-stranded DNA, which is enhanced in D2O, is compatible with a Type-II mechanism. SP is a known generator of singlet oxygen whose participation in the reaction is supported by the effects of quenchers and scavengers. In duplex DNA, piperidine-induced cleavage occurs with high selectivity at the 5'-G of GG and (less prominently) GA doublets. This behavior is characteristic of a Type-I process involving electron transfer from DNA to photoexcited SP molecules. The ability of SP to sensitize the formation of Type-I and Type-II photo-oxidation products from 2'-deoxyguanosine attests to the feasibility of competing mechanisms in DNA.

Alkalies↗
PubMed2005

Contribution of cytochrome P450 2D6 to 3,4-methylenedioxymethamphetamine disposition in humans: use of paroxetine as a metabolic inhibitor probe.

BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative typically used for recreational purposes. The participation of cytochrome P450 (CYP) 2D6 in the oxidative metabolism of MDMA may suggest an increased risk of acute toxicity in CYP2D6 poor metabolisers. This study was aimed at assessing the contribution of CYP2D6 to MDMA disposition in vivo using paroxetine as a metabolic probe inhibitor. Paroxetine, a CYP2D6 inhibitor, was repeatedly administered before MDMA administration. STUDY DESIGN: This was a randomised, double-blind, crossover, placebo-controlled trial conducted in seven healthy male volunteers who were CYP2D6 extensive metabolisers. Treatment conditions (paroxetine/MDMA and placebo/MDMA) were randomly assigned. Each volunteer participated in two 3-day sessions. On days 1, 2 and 3 subjects received a single oral dose of paroxetine or placebo 20 mg. On the third day, a single oral dose of MDMA 100 mg was administered in both paroxetine and placebo conditions. METHODS: Plasma concentration-time profiles and urinary recoveries of MDMA and its metabolites were measured, as well as plasma concentrations of paroxetine, (3S,4R)-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-piperidine, and (3S,4R)-4-(4-fluorophenyl)-3-(3-methoxy-4-hydroxyphenoxymethyl)-piperidine (HM-paroxetine). RESULTS: Paroxetine given before MDMA resulted in significant increases of MDMA area under the plasma concentration-time curve from 0 to 27 hours (AUC(27)) [23%], AUC from zero to infinity (AUC(infinity)) [27%] and maximum plasma concentration (C(max)) [17%], without significant differences in MDMA time to reach C(max) (t(max)). MDMA elimination-related pharmacokinetic parameters showed a significant reduction of MDMA elimination rate constant (K(e)) [-14%] and plasmatic clearance (CL(P)) [-29%]. In the case of 3,4-dihydroxymethamphetamine (HHMA), a 21% decrease in C(max) with no significant differences in AUC(27), AUC(infinity), K(e) and elimination half-life) were found. 4-Hydroxy-3-methoxymethamphetamine (HMMA) showed a decrease in plasma concentrations with a reduction in AUC(27) (-28%), AUC(infinity) (-20%) and C(max) (-46%). In the case of 3,4-methylenedioxyamphetamine (MDA) an increase in C(max) (17%) and AUC(27) (16%) was found. Following paroxetine pretreatment, the urinary recovery (0-45 hours) of MDMA increased by 11%; HHMA and HMMA urinary recoveries were 27% and 16% lower, respectively compared with placebo. The ratio of C(max) values of paroxetine and its metabolite on days 1 and 3 showed a 3-fold reduction, with no differences in t(max). DISCUSSION AND CONCLUSION: The contribution of CYP2D6 to MDMA metabolism in humans is not >30%, therefore other CYP isoenzymes may contribute to O-demethylenation of MDMA. Accordingly, the relevance of genetic polymorphism in CYP2D6 activity on MDMA effects and MDMA-induced acute toxicity should be examined as well as the interactions of other CYP2D6 substrates with MDMA, once the enzyme is inhibited. The pharmacokinetics of HM-paroxetine in humans after the administration of repeated doses is reported for the first time in this study.

Adult↗
PubMed2000

A solution-phase combinatorial synthesis of selective dopamine D4 ligands.

Utilizing combinatorial synthesis and a preparative LC-MS automated chromatography system we have prepared and purified a library of 4-[2-(1,2,4-oxadiazolyl)]piperidines that were designed to be novel and selective dopamine D4 ligands. In one round of synthesis we identified N-4-chlorobenzyl-4-[2-(3-(2-thienyl)-1,2, 4-oxadiazolyl)]piperidine with a Kd of 5 nM for the human D4 receptor.

Combinatorial Chemistry Techniques↗
PubMed1984

Species differences in the in vitro metabolism of phencyclidine.

The metabolism of 1-(1-phenylcyclohexyl)-piperidine (phencyclidine or PCP) by liver preparations from cat, monkey, rabbit and rat has been studied. 4-Phenyl-4-piperidinocyclohexanol (I), 1-1-phenylcyclohexyl-4-hydroxy-piperidine (II), N-(5-hydroxypentyl)-1-phenylcyclohexylamine (IX) and 5-(1-phenylcyclohexylamino)-valeric acid (X) were found in all species, but liver preparations of rat and rabbit were much more active than those of cat or monkey in metabolizing PCP. Only rabbit produced 4-(4'-hydroxypiperidino)-4-phenylcyclohexanol (III) in amounts detectable by g.l.c. Mass balance calculations of PCP, I, II, III, IX and X in the cat, monkey and rat indicate that other metabolic pathways not measured in this study are operative.

Animals↗
PubMed1995

Isolation and identification of seven metabolites of a water-soluble platelet aggregation inhibitor in rat urine.

1. Seven metabolites of 7-piperidino-1,2,3,4,5-tetrahydroimidazo[2,1- b]quinazolin-2-one dihydrochloride monohydrate (DN-9693) were isolated from rat urine by extraction with Amberlite XAD-2 and purification by silica gel and Sephadex LH-20 open-column chromatography and preparative high-performance liquid chromatography (hplc). The structure assignment of the metabolites was performed by field desorption mass spectrometry and 200-MHz Fourier transform nmr spectroscopic analysis and comparison with authentic standards when available. 2. DN-9693 underwent metabolism mainly at the piperidine ring to give the 4-hydroxypiperidine derivative (III) and 2-hydroxy-piperidine derivative, which is further metabolized to lactam (II) or delta-aminovaleric acid (V). The acyl side chain of V was shortened by beta-oxidation to form the 3-aminopropionic acid derivative (VII). V and/or VII underwent oxidative dealkylation to give the 7-amino derivative, which was conjugated with acetic acid to form the 7-acetylamino derivative (IV). DN-9693 also underwent hydrolysis of its lactam moiety to give VI. 3. The urinary excretion of III, V and VII was determined by liquid chromatography/electrochemistry (LC/EC) and V proved to be the major metabolite in rat urine. 4. A procedure is also presented for the identification of DN-9693 metabolites using LC/EC.

Animals↗
PubMed1993

Detection of free radicals in the blood of animals using extracorporeal circulation.

A method was designed to detect free radicals in circulating blood of animals using extracorporeal circulation and electron paramagnetic resonance (EPR). An arterial-venous shunt was inserted into male Wistar rats between the distal abdominal aorta and the inferior vena cava. The polyethylene tube of the shunt was flowed through a quartz EPR cell. The circulation was supported by manual pumping and maintained at a rate of 3 ml/min. No signal was detected in the blood of untreated rats. After a bolus injection of four spin labels, 2,2,6,6-tetramethyl-piperidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl, 3-carbamoyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl, and 3-carbamoyl-2,2,5,5-tetramethyl-pyrroline-1-oxyl, signals from each were detected. The intensity of the signal decreased exponentially and the half time was 23.9, 21.6, 47.1, 42.4 sec, respectively. After administration of ascorbic acid, ascorbyl radical signals were detected. This was enhanced by ethylenediaminetetraacetic acid-Fe or diethylenetriaminepentaacetic acid-Fe but not desferrioxamine-Fe. This assay system is useful in detecting free radicals either administered or generated in vivo.

Animals↗
PubMed2003

Novel sigma binding site ligands as inhibitors of cell proliferation in breast cancer.

Sigma receptors, namely sigma1 and sigma2, have been shown to be expressed in a variety of human cell lines playing a role in cell growth. In the human breast, they are absent in normal mammary tissue but expressed in tumors, particularly in the proliferating stage. The study presented here concerns nine newly synthesized ligands for sigma receptors. The compounds are of general structure consisting of: five (1alpha/1beta-arylalkyl)quinolizidines including two thioisosteres and four spiro-[3,4-dihydro-1,2,4-benzotriazino-3,4'-(1'-substituted) piperidines]. These compounds exhibited varying degrees of affinity for sigma receptors and were able to inhibit the growth of MCF-7 and MDA-MB 231 human breast cancer cell lines, in vitro. Good to moderate binding to at receptors occurred with all tested ligands. However, affinity for sigma2 appeared more evident with compounds FN/C-2 and FN/C-4 (spiro-[3,4-dihydro-1,2,4-benzotriazino-3,4'-(1'-substituted) piperidines] derivatives). In addition, higher cytotoxic activity of FN/C-2 and FN/C-4 with IC50 values below 100 microM in MCF-7 and lower than 40 microM in MDA-MB 231 was revealed. The data from the current study show that these novel sigma receptor ligands exhibit interesting cytotoxic activity and suggest their potential for development as antitumor agents.

Binding Sites↗
PubMed2006

Synthesis and antimelanoma activity of reversed amide analogues of N-acetyl-4-S-cysteaminylphenol.

The melanin biosynthetic pathway from tyrosine is a potential target for combating malignant melanoma. N-Acetyl-4-S-cysteaminylphenol 1 is a previously synthesized analogue of tyrosine that probably acts by this pathway. It interferes with cell growth and proliferation via selective oxidation in melanocytes to an oquinone that can alkylate cellular nucleophiles. We previously synthesized a range of analogues of the original lead compound 1 most of which displayed greater cytotoxicity than 1. Eighteen new analogues with the amide group reversed have now been synthesized and tested for antimelanoma activity. Most of these reverse amides showed greater cytotoxicity than N-acetyl-4-S-cysteaminylphenol towards five representative melanoma cell lines. The highest cytotoxicity was observed for the piperidine and hexamethyleneimine derivatives 7, 8, 12, 13, and 17 and the catechol 18. The most active compound, 7, had cytotoxicity comparable to cisplatin against the five melanoma cell lines. The moderate activity of 7 and 18 against SK-Mel-24 (non-tyrosinase containing) and an ovarian cell line suggests that interference with the melanin pathway may not be the only mode of action of these compounds. Assays of some of the compounds as substrates for tyrosinase showed that the catechol 18 was the best substrate and that the piperidine derivative 7 was the best substrate of the phenolic compounds synthesized.

Amides↗
PubMed1999

Characterization of the effects of polyamines on [125I]MK-801 binding to recombinant N-methyl-D-aspartate receptors.

The assembly of heterogeneous populations of native N-methyl-D-aspartate receptors results in receptors with multiple pharmacological properties dependent on subunit combinations. Using stably transfected ML(tk-) mouse fibroblasts expressing N-methyl-D-aspartate R1a and either R2A or R2B, we evaluated polyamine effects on [125I]dizocilpine (MK-801) binding to determine subunit-specific pharmacological characteristics. The polyamine agonists spermine and spermidine produced biphasic concentration response curves in rat brain membrane: low concentrations (<100 microM) enhanced [125I]MK-801 binding and higher concentrations (>100 microM) inhibited binding. Polyamine agonists did not affect [125I]MK-801 binding in NR1a/NR2A, whereas spermine and spermidine did produce enhancement, and, at higher concentrations, inhibition of binding in NR1a/NR2B. The polyamine 1,5-(diethylamino)piperidine is thought to be selective for the agonist polyamine site and only enhanced [125I]MK-801 binding in brain membranes (EC50 = 9.6 microM). However, 1,5-(diethylamino)piperidine inhibited [125I]MK-801 binding (IC50 = 8.0 microM) in NR1:NR2A receptors and produced a small increase followed by a modest decrease in binding to NR1a/NR2B receptors. In brain membranes, the polyamine antagonist arcaine inhibited [125I]MK-801 binding (IC50 = 4.6 microM). Similar effects were demonstrated in both NR1:NR2A and NR1:NR2B receptors (IC50 = 8. 4 and 14.1 microM, respectively) and agonists decreased the affinity of arcaine in both receptor preparations. These results suggest that the stimulatory effects of polyamines on recombinant receptors are influenced by the NR2 subunit, and that NR1:NR2A does not contain a positive modulatory site. However, the inhibitory effects of polyamine antagonists are similar in both subunit combinations. Furthermore, native NMDA receptors pharmacology cannot be modeled by simple NR1:NR2A or NR1:NR2B combinations.

Algorithms↗
PubMed1976

A method for radioimmunological assay of glisoxepide (author's transl).

A radioimmunoassay for the antidiabetic drug 3-(4-[beta-(5-methyl-isoxazol-3-carboxyamido)-ethyl]-benzenesulfonyl)-ureido-piperidine-4-carboxic acid (glisoxepide, I, Pro-Diaban) is described. Antisera were obtained by immunizing rabbits with a piperidine carboxylic acid analogue of glisoxepide coupled to bovine serum albumine. The carboxylic acid analogue coupled to [3H]-1-tyrosine methyl ester was used as the tracer. Antisera with high sensitivity were obtained. With some glisoxepide analogues the specificity of the antisera was investigated. For good binding the isoxazole and the benzene ring as well as the appropriate distance between both rings are essential. The assay can be carried out without extraction of the compound from the serum. Dextran coated charcoal is used for separation of free and bound glisoxepide.

Cross Reactions↗
PubMed2002

GC/MS investigations of the minor constituents of Piper guineense stem.

Chemical investigations by GC/MS-analysis of stem extracts of Piper guineense resulted in the detection and identification of thirty-nine new constituents of the stem, apart from previously isolated constituents. These are isobutyl, pyrrolidyl and piperidyl amide alkaloids. Fifteen new natural products have been identified. Four of these natural products have been designated iyeremide A and B (these are pyrrolidine and piperidine analogues of pellitorine) and cycloguineense A and B, which are also piperidine analogues of cyclostachine A and B. There is a need to confirm the structures of some of these new constituents by synthesis. Apart from these amide alkaloids, many volatile oil components-monoterpenes, sesquiterpenes, terpenoids, lignans and sterols--were detected.

Alkaloids↗
PubMed1992

Tolerance to the cataleptic effect of the N-methyl-D-aspartate (NMDA) receptor antagonists in pigeons: cross-tolerance between PCP-like compounds and competitive NMDA antagonists.

The effects of chronic administration of phencyclidine (PCP) or CGS 19755 (cis-4-phosphonomethyl-2-piperidine-carboxylic acid) on the cataleptic effects of N-methyl-D-aspartate (NMDA) receptor antagonists were studied in pigeons. PCP, a channel blocker of the NMDA receptor complex, or CGS 19755, a competitive NMDA antagonist, was administered i.m. to separate groups of pigeons each day. Tolerance developed to the cataleptic effects in both PCP- and CGS 19755-treated pigeons. PCP tolerance was characterized initially by 5-fold rightward shift and, with an increased chronic PCP dose, a complete downward shift of the PCP dose-effect curve. CGS 19755 tolerance was indicated by a 10-fold rightward shift of its dose-cataleptic effect curve. Cross-tolerance was obtained from PCP to other PCP-like compounds including dizocilpine (MK 801), ketamine, dextrorphan, 1-(2-thienyl)-cyclohexyl-piperidine and [(+)-SKF 10047] [(+)-N-allyl-normetazocine] as well as to the competitive NMDA antagonist, CGS 19755. Cross-tolerance also developed from CGS 19755 to another competitive NMDA antagonist, CGP 40116 [D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] as well as to PCP-like compounds. The pharmacological selectivity of tolerance was evident because there was equal sensitivity to etomidate or pentobarbital in tolerant and nontolerant pigeons. The symmetric cross-tolerance between PCP-like compounds and competitive NMDA antagonists suggests the cataleptic effects of the two classes of NMDA antagonists are probably mediated via a similar mechanism of inhibition of neurotransmission at the NMDA excitatory synapse.

Animals↗
PubMed1992

Design of an irreversible affinity ligand for the phencyclidine recognition site on N-methyl-D-aspartate-type glutamate receptors.

A series of 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) analogs were synthesized with the aim of developing a potent ligand for the N-methyl-D-aspartate glutamate receptor subtype. The piperidine moiety of TCP was substituted at the nitrogen position with aliphatic chains of different length or with various polar groups. A correlation between the decrease in the potency of displacement of [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-im ine maleate (MK-801) binding from bovine cortex membranes and the increase of length or polarity of the aliphatic chain was observed. Isonitrile, isothiocyanate and isoselenocyanate groups were substituted at position 4 of the thiophene ring, and the relative binding affinity and alkylating potencies of the derivatized compounds were studied. Among this set of compounds, the one carrying an isothiocyanate group at position 4 of the thiophene ring of the N-ethyl analog of TCP yielded the most efficient alkylating agent, demonstrated by its ability to irreversibly block up to 80% of the [3H]MK-801 binding sites. This affinity ligand did not significantly affect other ligand binding sites of the same N-methyl-D-aspartate receptor complex or of other receptor systems, further demonstrating its functional specificity as a potent alkylating probe for the TCP/MK-801 recognition site. Studies with a radiolabeled adduct of this isothiocyanate N-ethyl derivative, however, indicate that a substantial level of nonspecific covalent incorporation into the membranes occurs at concentrations as low as 10 nM, thereby obscuring any possibility of detecting a specifically labeled protein species.

Affinity Labels↗
PubMed1991

Effects of drugs that bind to PCP and sigma receptors on punished responding.

Several arylcyclohexylamines and opioid benzomorphans that bind to phencyclidine (PCP) receptors were studied for their effects on punished and unpunished responding maintained under fixed-interval schedules of food presentation. All of these drugs increased both punished and unpunished responding, although higher doses decreased responding. The order of potency for increasing punished responding was MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzoa(a,d)-cyclohepten-5,1 0-imine] greater than [1-[1-(2-thienyl)cyclohexyl]piperidine] = PCP greater than (+)-N-allylnormetazocine = (-)-N-allynormetazocine. There was a high correlation (0.95) between the relative potency of these drugs in increasing punished responding and their relative affinity for PCP receptors. Because some of these drugs also bind to sigma receptors, drugs with a high affinity for sigma receptors, such as haloperidol, BD 737 [1S,2R-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N- methyl-2-(1-pyrrolidinyl) cyclohexylamine] and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, were also studied for their effects on punished and unpunished responding. These drugs produced only rate-decreasing effects. The correlation between the relative potency of drugs in increasing punished responding and their relative affinity for sigma receptors was low (-0.19). These data suggest that the PCP receptor is involved in some drug-induced increases in punished responding.

Animals↗
PubMed1991

Sigma receptor ligands inhibit rat tail artery contractile responses by multiple mechanisms.

The goal of this study was to further explore the mechanism of action by which several sigma ligand inhibit vascular contractile responses. By using the rat tail artery, the following sigma receptor ligands were tested: haloperidol; (+)-3-(3-hydroxyphenyl)-N- (1-propyl)piperidine; 1,3-di-ortho-tolyl-guanidine; cis-9- [3-(3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride; (+/-)-alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; and the two newly identified sigma ligands, N-(1-adamant-1- yl)-N'-(2-iodophenyl)guanidine and 2-amino-(3-phenyl)-3,4-dihydroquinazoline. We first tested the possibility that this inhibitory effect is mediated by an action on muscarinic receptors or an endothelium-dependent mechanism. However, inhibitory responses caused by either haloperidol or (+/-)-alpha-(4-fluorophenyl)- 4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol were unaffected by the muscarinic antagonist atropine, 10(-7) M, or by removal of the endothelium. We then explored the pharmacological profile of the inhibitory effect using several different contractile agents. Except for (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine which did not affect serotonin-evoked contractions, all ligands used caused an inhibition of norepinephrine-, serotonin- and KCl-induced contractile responses. Each sigma ligand exhibited a distinct individual inhibitory profile with respect to preferential actions on either norepinephrine- or serotonin-induced contractions, suggesting that these ligands act by several mechanisms to inhibit contractile responses in the rat tail artery. The multiple functional effects of this group of putative sigma receptor ligands suggests that they have only limited utility for exploration of the potential physiological role of the sigma receptor.

Animals↗
PubMed1991

Identification and characterization of two sigma-like binding sites in the mouse neuroblastoma x rat glioma hybrid cell line NG108-15.

NG108-15 cells were shown to possess high affinity binding sites for 1,3-di(2-[5-3H]tolyl)guanidine ([3H]DTG), a selective sigma ligand (Kd = 23 nM; maximal number of binding sites = 15.6 pmol/mg). The rank order of potency of drugs at this site was DTG greater than haloperidol greater than pentazocine greater than 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP] greater than phencyclidine (PCP) greater than metaphit greater than (-)-3-PPP greater than (-)-N-allylnormetazocine [(-)-SKF 10,047] greater than (-)-butaclamol greater than (+)-butaclamol greater than (+)-SKF 10,047 greater than dizolcipine (MK 801 [5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine- maleate]) greater than ketamine. Both, Kd value and pattern of ligand selectivity suggest a close relationship to sigma sites in rodent brain. However, in comparison to sigma sites in brain stereoselectivity for the benzomorphan, SKF 10,047 was reversed and the affinities for benzomorphans were only moderate to low. Thus, sigma binding sites in NG108-15 cells seem to correspond to recently detected sigma sites in a pheochromocytoma cell line (PC12). [3H]-1-(2-thienyl)-cyclohexyl]piperidine ([3H]TCP), a PCP receptor-selective ligand binds to NG108-15 cells with moderate affinity (Kd = 139 nM; maximal number of binding sites = 4.7 pmol/mg of protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Biotransformation of sufentanil in liver microsomes of rats, dogs, and humans.

The biotransformation of sufentanil (SUF), an analog of the synthetic opioids fentanyl and alfentanil, was investigated in liver microsomes of rats, dogs, and humans. The drug was extensively metabolized and the metabolism was found to be very similar, both kinetically and metabolically, in the three species. The initial metabolism of SUF occurred monophasically in man and dog and biphasically in the rat over a concentration range of 0.13-20.1 microM. The apparent Vm values were 7.30 and 6.15 nmol metabolized.min-1.mg protein-1, and the apparent Km values were 4.98 microM and 15.2 microM for dog and human microsomes, respectively. In rat microsomes, apparent Km values were 0.10 and 20.8 microM, and the apparent Vm values were 0.10 and 7.32 nmol metabolized.min-1.mg protein-1 for the high and low affinity site, respectively. The major metabolic pathways were similar in the three species and included oxidative N-dealkylation at the piperidine nitrogen, oxidative N-dealkylation of the piperidine ring from the phenylpropanamide nitrogen, oxidative O-demethylation, and aromatic hydroxylation. Desmethyl-SUF was formed at the shorter incubation times but quickly metabolized into secondary metabolites. The major metabolites which could be detected at the end of the incubation were N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, N-[4-(hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide, and N-phenylpropanamide. The relevance of the in vitro results is discussed in relation to previous in vivo studies of the metabolism of SUF in rats, dogs, and humans.

Analgesics↗
PubMed1990

[Biotransformation of the trapidil (rocornal) derivative AR 12463 in the rat].

After p.o. administration of 5-piperidino-7-[N-pentyl-N-(beta- hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine (1; AR 12463) more than 15 metabolites were isolated from urine and feces of male Wistar rats. Only small amounts of unchanged 1 were observed. The structure of 12 metabolites was elucidated or proposed on the basis of UV-, 13C NMR- and mass spectra. Main metabolites are 5-piperidin-4'-olyl-7-[N-pentyl-N-(beta- hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine and 5-piperidin-4'-olyl-7-[N-pent-4-olyl-N-(beta-hydroxyet hyl)]amino-s- triazolo[1,5-a]pyrimidine. The other metabolites are mainly hydroxy- or ketopentyl derivatives and piperidinoles or piperidinones, respectively. Conjugates of most of the metabolites were identified, but the ratio phase-I/II metabolites was about 3:1. In contrast to trapidil, 5-methyl-7-diethylamino-s- triazolo[1,5-a]pyrimidine, no hydroxy derivatives of the bicyclic system were observed. The major part of unchanged 1 and metabolites is excreted via kidneys.

Adsorption↗