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PubMed1978

Metabolites of piperidine in rat urine.

Piperidine is one of pharmacologically active biogenic amines. While two pathways for piperidine production have been reported, little is known about metabolism of the compound. In the present study, piperidine and its hydroxylated, conjugated and unknown metabolites were detected in rat urine by radiochromatographic analysis. Using GC-MS technique, it was confirmed that 3-hydroxypiperidine and 4-hydroxypiperidine are major metabolites of piperidine of either exogenous or endogenous origin. The findings substantiate the existence of a mechanism which inactivates piperidine in the living body, since both metabolites lack the potent pharmacological activities as those induced by piperidine.

Acetylation↗
PubMedDate not supplied

Application of chemical cytochrome P-450 model systems to studies on drug metabolism. IV. Mechanism of piperidine metabolism pathways via an iminium intermediate.

Oxidations of the piperidine ring by chemical model and liver microsomal systems were investigated with a simple piperidine derivative, N-benzylpiperidine (BP) (3), as the substrate in order to probe the generality and the mechanism of the biotransformation of the piperidine ring. The piperidine ring of BP (3) as well as that of phencyclidine (1) was suggested to be oxidized to a ketone at the beta-position in the meso-tetraphenylporphinatoiron(III) chloride system, and the reaction was expected to occur in the liver microsomal system. The beta-oxo formation was observed directly in the liver microsomal system, and found to be dependent on cytochrome P-450. Then it was suggested that the piperidine-beta-oxo formation was a general oxidation pathway of the piperidine biotransformation. Hydrogen abstraction in the reaction was not a rate-determining step. Therefore, we presumed a possible mechanism of beta-oxo formation via BP-iminium (21). From the comparative study on the reactivities of dipropylbenzylamine (DPB) (18) and BP (3), and the stabilities of iminium (Im+) species of BP (3) and DPB (18), it was suggested that BP-Im+ (21) was relatively stable and was the most likely precursor of BP-beta-oxo (6). BP-Im+ (21) and its free base, enamine (29), afforded large amounts of BP-beta-oxo as well as BP-alpha-oxo (9) in the chemical model and the microsomal systems. This evidence supported the iminium-enamine mechanism expressed as scheme III.

Animals↗
PubMed2005

The use of liquid chromatography-atmospheric pressure chemical ionization mass spectrometry to explore the in vitro metabolism of cyanoalkyl piperidine derivatives.

A LC/MS method using atmospheric pressure chemical ionization, positive ion mode and full scan to measure the in vitro metabolic stability of cyanoalkyl functionalized compounds with the human liver microsomes was employed. Percentage metabolism examined for the five cyanoalkyl piperidines revealed the optimal chain length and positioning of these functions to produce the most metabolically stable compound. The 4-cyanomethyl piperidine derivative was the most stable compound with 15% metabolism after 15 min incubation with human liver microsomes. In general, the major metabolites formed from the cyanoalkyl piperidine derivatives were due to oxidation of the cyanoalkyl chain or the piperidine fragment, resulting in a M+16 ion. However, the 2-cyanomethyl piperidine derivative exhibited an interesting biotransformation pathway with unusual metabolite peaks corresponding to M+5, M-11 and M+21 ions. Data-dependent MS/MS scanning was used to generate daughter ion spectra from the parent compound and its metabolite peaks. Based on the fragmentation analysis, a carboxylic acid, aldehyde and oxidative metabolite of the carboxylic acid structure have been proposed for M+5, M-11 and M+21 ions, respectively.

Chromatography, Liquid↗
PubMed1980

Seasonal and activity-dependent variations of piperidine levels in the amphibian brain.

Piperidine is one of biogenic amines possessing nicotine-like synaptotropic actions on the nervous systems. Since piperidine produces multiplex physiological actions, a role for the amine as a modulator in neuroendocrine as well as neuronal functions has been supposed. In the present study, piperidine levels in the amphobian brains during activity and hibernation were examined by use of a mass fragmentographic technique and it was found that the brain piperidine concentrations significantly increased in the cold season especially during hibernation. The significance of the findings is discussed with respect to the hypnogenic effect of piperidine.

Animals↗
PubMed1979

Actions of piperidine and dimethylphenylpiperazinium (DMPP) on afferent discharges of the cat's carotid body.

Chemoreceptor discharges were recorded in vivo from fine filaments of carotid sinus nerve; their frequency was used as index of receptor activity. Effects of piperidine on chemoreceptors were studied and compared with those of dimethylphenylpiperazinium (DMPP) on chemoreceptors in adult cats. Intracarotid-arterial injections of piperidine produced a transient increase in chemoreceptor discharges, the threshold dose ranging from 10 to 50 microgram i.a. The excitatory effect of piperidine was not affected by atropine, hexamethonium or GABA. DMPP (0.2-0.5 microgram i.a.) induced a marked increase in chemoreceptor discharges, which was abolished by hexamethonium, but not by atropine. DMPP ((2--5 microgram i.a.) induced sinus baroreceptor excitation, but piperidine did not. The results indicate that piperidine exerted excitatory effects on carotid body chemoreceptors, possibly acting on nerve endings of chemoreceptor afferent fibers.

Animals↗
PubMed1982

The excitatory actions of a series of piperidine dicarboxylates on central neurons of the rat, snail, leech and horseshoe crab and on crab neuromuscular junction.

1. Intracellular recordings were made from Helix, Hirudo and Limulus central neurons and from Eupagurus leg muscle and extracellular recordings from rat lateral geniculate neurons. The actions of 2,3-, 2,4-, 2,5- and 2,6-piperidine dicarboxylates were tested on those preparations for both direct effects and interactions with the response to L-glutamate. 2. All four piperidine analogues were devoid of either reproducible direct or indirect effects on Helix and Limulus neurons save that the 2,5-analogue did mimic the action of L-glutamate on Limulus neurons which were inhibited by glutamate. 3. On Hirudo and rat neurons and on Eupagurus muscle, all four piperidines mimicked the action of L-glutamate, all were weak agonists on rat neurones while on Hirudo neurons the 2,5-analogue was the most potent but on Eupagurus muscle, the 2,3- and 2,6-analogues were the most potent. 4. All four piperidines potentiated the action of L-glutamate on rat and Hirudo neurons and on Eupagurus leg muscle and of muscle ejps. 5. The piperidine analogues indicate that there are differences between the glutamate receptors used in the present study and provide some supportive evidence that the preferred conformation for glutamate on crab leg muscle is partially folded while for Hirudo neurons it is more extended.

Animals↗
PubMed2002

Anaerobic degradation of pyrrolidine and piperidine coupled with nitrate reduction.

Biodegradability of secondary amines (pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine) under anaerobic conditions was examined in microbial consortia from six different environmental sites. The consortia degraded pyrrolidine and piperidine under denitrifying conditions. Enrichment cultures were established by repeatedly sub-culturing the consortia on pyrrolidine or piperidine in the presence of nitrate. The enrichments strictly required nitrate for the anaerobic degradation and utilized pyrrolidine or piperidine as a carbon, nitrogen, and energy source for their anaerobic growths. The anaerobic degradation of pyrrolidine and piperidine reduced nitrate to nitrogen gas, indicating that these anaerobic degradations were coupled with a respiratory nitrate reduction.

Bacteria, Anaerobic↗
PubMed2002

Asymmetric carbon-carbon bond formations in conjugate additions of lithiated N-Boc allylic and benzylic amines to nitroalkenes: enantioselective synthesis of substituted piperidines, pyrrolidines, and pyrimidinones.

(-)-Sparteine mediated lithiations of N-Boc-allylic and benzylic amines provide configurationally stable intermediates which on conjugate additions to nitroalkenes provide highly enantioenriched enecarbamate products in good yields, and with high diastereoselectivities. Straightforward transformations of these adducts offer general routes to substituted 3,4-substituted piperidines, 3,4-substituted pyrrolidines, and 4,5-substituted pyrimidinones. Diastereoselective substitutions of intermediate lactams followed by reduction provide 3,4,5-substituted piperidines and 3,4-trisubstituted pyrrolidines. Lithiation adjacent to nitrogen of 3,4-substituted piperidines and pyrrolidines followed by diastereoselective substitution opens a route to 2,4,5- and 2,4,5,6-substituted piperidines as well as 2,3,4- and 2,3,4,5-substituted pyrrolidines. The enantiomers of the enecarbamate and 3,4-substituted piperidine products may be accessed by stannylation/transmetalation sequences as well as by further manipulation of 4-substituted piperidones. The methodology is used to synthesize both enantiomers of an aspartic peptidase inhibitor intermediate, 3-hydroxy-4-phenylpiperidine, as well as the antidepressant (+)-femoxetine.

Alkenes↗
PubMed1996

Novel potent sigma 1 ligands: N-[omega-(tetralin-1-yl)alkyl]piperidine derivatives.

A series of substituted N-[(tetralin-1-yl)alkyl]piperidines and a number of related N-di-n-propyl-[(tetralin-1-yl)alkyl]amines were prepared. Structural modifications such as piperidine substitutions, intermediate chain lengthening, and the nature of the aromatic ring were explored in order to identify structural requirements for selective sigma 1 affinity. They were tested in radioligand binding assays on sigma 1, 5-HT1A and 5-HT2 serotonergic, PCP (phencyclidine), and D-2 dopaminergic receptors. Almost all the compounds reported here showed a high to superpotent sigma 1 affinity, and some compounds also demonstrated a widespread selectivity over the other receptors. In [3H]-(+)-pentazocine binding, 3,3-dimethyl-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n- propyl] piperidine (24) and 3,3-dimethyl-1-[4-(1,2,3,4-tetrahydronaphthalen-1-yl)-n- butyl]piperidine (26) reached the lowest Ki values (0.4 and 0.8 nM, respectively); compound 24 also demonstrated a considerable PCP affinity (Ki = 34.2 nM), whereas compound 26 was suitably selective. Furthermore the presence of a 4-benzyl substituent on the piperidine ring (compound 16, Ki = 3.9 nM on sigma 1 sites) caused an increase in 5-HT1A affinity (Ki < 0.14 nM).

Animals↗
PubMed1998

Investigation of the N-substituent conformation governing potency and mu receptor subtype-selectivity in (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists.

A study of the binding site requirements associated with the N-substituent of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) derivatives was undertaken using a set of rigid vs flexible N-substituents. The study showed that compounds 7-9 bearing the trans-cinnamyl N-substituent most closely reproduced the potency at the opioid receptor of the flexible N-propylphenyl or N-propylcyclohexyl analogues previously reported. Neither the N-substituted cis-cinnamyl nor the cis-phenylcyclopropylmethyl compounds 10 and 11, respectively, showed high affinity for the opioid receptor. However, the N-trans-phenylcyclopropylmethyl compound 12 closely approximated the affinity of compounds 7-9. Additionally, we found that free rotation of the phenyl ring is necessary for high affinity binding and mu receptor subtype selectivity as the planar N-substituted thianaphthylmethyl and benzofuranylmethyl compounds 13 and 14 had significantly lower binding affinities. Altogether, these findings suggest that the high binding affinity, selectivity, and antagonist potency of N-propylphenyl or N-propylcyclohexyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) are achieved via a conformation wherein the connecting chain of the N-substituents is extended away from piperidine nitrogen with the appended ring system rotated out-of-plane relative to the connecting chain atoms. This conformation is quite similar to that observed in the solid state for 5, as determined by single crystal X-ray analysis. Additionally, it was found that, unlike naltrexone, N-substituents bearing secondary carbons attached directly to the piperidine nitrogen of 4 suffer dramatic losses of potency vs analogues not substituted in this manner. Using a functional assay which measured stimulation or inhibition of [35S]GTP-gamma-S binding, we show that the trans-cinnamyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) retain opioid pure antagonist activity and possess picomolar antagonist potency at the mu receptor.

Animals↗
PubMed1984

The pharmacology of the piperidine dicarboxylates on the crustacean neuromuscular junction.

The effects of the four cis-piperidine dicarboxylate analogues (PDAs) on the neuromuscular junction of the hermit crab (Eupagurus bernhardus) were examined. Intracellular recordings of evoked excitatory junction potentials (EJPs) and the membrane potential were made. All four analogues were active as agonists and depolarized the fibre membrane. The dose-response curves for the 2,3 and 2,6-piperidine dicarboxylates were similar to that for L-glutamate but were one tenth as potent. The dose-response curves for the 2,4 and 2,5-piperidine dicarboxylates had shallower gradients and lower maxima indicating lower potencies. The piperidine dicarboxylates non-competitively antagonized and glutamate-induced potential and reversibly attenuated the amplitude of the junction potential, with no change in membrane input resistance. The decrease in amplitude of the glutamate-induced potentials produced by a train of ionophoretic pulses was reversibly blocked by incubation with any of the dicarboxylates. The results indicate that the piperidine dicarboxylates prevent the development of receptor desensitization. The significance of these findings is discussed.

Animals↗
PubMed2005

Selective methodologies for the synthesis of biologically active piperidinic compounds.

The synthesis of optically active substituted piperidines has been achieved by using four different methodologies. The first one is an intramolecular nucleophilic displacement of activated alcohol moieties that was used to build up the piperidine ring of (-)-prosophylline and (-)-slaframine, and the second one is a ring-closing metathesis of unsaturated amines which was employed in the synthesis of (+)-sedamine and 4a,5-dihydrostreptazoline. The third methodology is the alpha-functionalization of N-Boc piperidines which was particularly useful in the synthesis of argatroban, and the fourth one is a ring expansion of prolinols to 3-chloropiperidines or 3-hydroxypiperidines which was utilized to synthesize (-)-paroxetine, (-)-pseudoconhydrine, the piperidine ring of (-)-velbanamine and (+)-zamifenacin.

Alkaloids↗
PubMed2006

Rhodococcus sp. strain TM1 plays a synergistic role in the degradation of piperidine by Mycobacterium sp. strain THO100.

Mycobacterium sp. strain THO100 and Rhodococcus sp. strain TM1 were isolated from a morpholine-containing enrichment culture of activated sewage sludge. Strain THO100, but not strain TM1, was able to degrade alicyclic amines such as morpholine, piperidine, and pyrrolidine. The mixed strains THO100 and TM1 showed a better growth on piperidine as the substrate than the pure strain THO100 because strain TM1 was able to reduce the level of glutaraldehyde (GA) produced during piperidine degradation. GA was toxic to strain THO100 (IC(50) = 28.3 microM) but less toxic to strain TM1 (IC(50) = 215 microM). Strain THO100 possessed constitutive semialdehyde dehydrogenases, namely Sad1 and Sad2, whose activities toward succinic semialdehyde (SSA) were strongly inhibited by GA. The two isozymes were identified as catalase-peroxidase (KatG = Sad1) and semialdehyde dehydrogenase (Sad2) based on mass spectrometric analyses of tryptic peptides and database searches of the partial DNA sequences of their genes. In contrast, strain TM1 containing another constitutive enzyme Gad1 could oxidize both SSA and GA. This study suggested that strain TM1 possessing Gad1 played a synergistic role in reducing the toxic and inhibitory effects of GA produced in the degradation of piperidine by strain THO100.

Amines↗
PubMed1999

Cytoplasmic determinants of piperidine blocking affinity for N-type calcium channels.

Piperidines are a relatively novel class of calcium channel blockers which act at a unique receptor site associated with the calcium channel alpha1 subunit. Calcium channel blocking affinities ranging from subnanomolar to several hundred micromolar have been reported in the literature, suggesting that piperidine block is highly sensitive to the cellular environment experienced by the channel. Here, I have investigated some of the cytoplasmic determinants of haloperidol block of N-type calcium channels expressed in human embryonic kidney cells. In perforated patch clamp recordings, haloperidol blocks N-type calcium channels with an inhibition constant of 120 microM. Upon internal dialysis with chloride containing pipette solution, the blocking affinity increases by 40-fold. This effect could be attributed in part to the presence of internal chloride ions, as replacement of intracellular chloride with methanesulfonate reduced haloperidol blocking affinity by almost one order of magnitude. Tonic inhibition of N-type channels by Gbetagamma subunits further enhanced the blocking effects of haloperidol, suggesting the possibility of direct effects of Gbetagamma binding on the local environment of the piperidine receptor site. Overall, depending on the cytoplasmic environment experienced by the channel, the blocking affinity of N-type calcium channels for haloperidol may vary by more than two orders of magnitude. Thus, absolute blocking affinities at the piperidine receptor site must be interpreted cautiously and in the context of the particular experimental setting.

Binding Sites↗
PubMed1990

Piperidine discriminates between the transient and the persistent components of the ACh-induced chloride current in Aplysia neurons.

ACh-induced Cl- -current (ICl) is well known to desensitize with two components: an initial fast phase followed by a second, more slowly developing phase. In the present study, the influence of piperidine, a normal constituent in vertebrates and invertebrates, on ACh-induced ICl in isolated neurons of Aplysia was investigated by using the concentration clamp in combination with the voltage clamp technique. Pretreatment with piperidine in doses greater than 2 X 10(-4)M depressed the transient ACh-induced ICl but had little effect on the persistent ICl. Kinetic study of the desensitization phase of ACh-induced ICl showed that the slow time constant of the desensitization phase of ACh-induced ICl was not altered by pretreatment with piperidine. The present results indicate that piperidine can discriminate between the fast transient and slow persistent components of ACh-induced ICl in Aplysia neurons, and also suggest that two components of the desensitization phase of ACh-induced ICl function in an independent manner.

Acetylcholine↗
PubMed1977

The action of piperidine on muscle spindles in the rat.

Piperidine hydrochloride induced discharge in primary and secondary endings of muscle spindles in rat tailbase muscle preparations. The threshold concentration for primary endings (2.0 X 10(-5) g/ml) was below that for secondary endings (4.0 X 10(-5) g/ml). The effect of piperidine was antagonised by tubocurarine but not by atropine. The action of piperidine on primary and secondary endings responding to 'ramp-and-hold' stretch was predominantly on the static component of excitation, and usually in the absence of any concomitant enhancement of the dynamic effect. This effect was opposite to that induced by succinylcholine. A possible action of piperidine at cholinoceptive sites of the nicotinic type and associated with gamma-trial fusimotor terminals is discussed.

Action Potentials↗
PubMed1987

Piperidine: a microelectrophoretic study in the mammalian brain.

Using unit recording and electrophoretic techniques, the action of piperidine on unit activity of the brain of the rat was studied. Piperidine excited 31%, and inhibited 4% of cortical cells tested. In the hippocampus and caudate nucleus, piperidine excited larger proportions of the cells tested. The actions of piperidine were blocked by tetraethylammonium but not by scopolamine.

Acetylcholine↗
PubMed1995

Syntheses, activity and modeling studies of 3- and 4-(sulfo- and sulfonamidoalkyl)pyridine and piperidine-2-carboxylic acid derivatives as analogs of NMDA receptor antagonists.

A series of 3- and 4-(sulfo- and sulfonamidoalkyl)pyridine and piperidine-2-carboxylic acid derivatives as analogs of NMDA receptor antagonists was prepared. Affinity for the NMDA receptor was determined by binding assays using the specific radioligand [3H] (2SR,4RS)-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS-19755). The 3-alkylsulfonyl moiety was introduced by selective reduction of a carboxylic acid function followed by bromination, substitution by Na2SO3 and catalytic reduction. For the 4-alkylsulfonic derivatives the crucial step was the introduction of the 2-cyano function and its further conversion to 2-carboxylic acid. The most potent compound of the series was the pyridine (11a) [4-(sulfomethyl)pyridine-2-carboxylic acid] with a modest IC50 of 40 microM. A molecular modeling study has been undertaken to understand the pharmacological results. In a first step, a comparative modeling study of the active pyridine and the poorly active piperidine sulfonic acid derivatives 11a and 10a [4-(sulfomethyl)piperidine-2-carboxylic acid] and of the phosphonic homologues was performed. We propose that the binding geometry of the sulfonic moiety within the NMDA receptor is different from that of the phosphonic containing antagonists. In order to test this assumption, we have made, in a second step, a complete conformational analysis of the sulfonic acid derivatives, as well as some analogs taken from the literature, either active or inactive as NMDA antagonists. A preferred conformation of the sulfonic acids is proposed.

Binding, Competitive↗