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1.
Science ; 224(4647): 405-7, 1984 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-6608790

RESUMEN

Hydroxylated derivatives of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a nigrostriatal neurotoxin in humans and primates, noncompetitively inhibited dihydropteridine reductase from human liver and rat striatal synaptosomes in vitro at micromolar concentrations. In contrast, MPTP and its chloro- and norderivatives did not inhibit this enzyme at lower than millimolar concentrations. Dihydropteridine reductase converts dihydrobiopterin to tetrahydrobiopterin, the required cofactor for the hydroxylation of aromatic amino acids during the synthesis of dopamine and serotonin.


Asunto(s)
Dihidropteridina Reductasa/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , Piridinas/farmacología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Cuerpo Estriado/enzimología , Humanos , Hidroxilación , Hígado/enzimología , NAD/metabolismo , Ratas , Relación Estructura-Actividad , Sinaptosomas/enzimología
2.
Pharmacol Ther ; 49(1-2): 105-9, 1991.
Artículo en Inglés | MEDLINE | ID: mdl-1852784

RESUMEN

Chemical structures of colchicine and related analogs, including allo-compounds with a six-membered ring, are presented here with correct absolute configurations, showing the natural representatives as a S-atropisomers. Spectral data, synthesis, biosynthesis, and metabolism of colchicine are discussed. Structural requirements required for these compounds to inhibit polymerization of tubulin and binding of radiolabeled colchicine in vitro are presented.


Asunto(s)
Colchicina/química , Animales , Colchicina/metabolismo , Colchicina/farmacología , Humanos
3.
Acta Neurol Scand Suppl ; 176: 74-84, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-11261809

RESUMEN

Phenserine, a phenylcarbamate of physostigmine, is a new potent and highly selective acetylcholinesterase (AChE) inhibitor, with a > 50-fold activity versus butyrylcholinesterase (BChE), in clinical trials for the treatment of Alzheimer's disease (AD). Compared to physostigmine and tacrine, it is less toxic and robustly enhances cognition in animal models. To determine the time-dependent effects of phenserine on cholinergic function, AChE activity, brain and plasma drug levels and brain extracellular acetylcholine (ACh) concentrations were measured in rats before and after phenserine administration. Additionally, its maximum tolerated dose, compared to physostigmine and tacrine, was determined. Following i.v. dosing, brain drug levels were 10-fold higher than those achieved in plasma, peaked within 5 min and rapidly declined with half-lives of 8.5 and 12.6 min, respectively. In contrast, a high (> 70%) and long-lasting inhibition of AChE was achieved (half-life > 8.25 h). A comparison between the time-dependent plasma AChE inhibition achieved after similar oral and i.v. doses provided an estimate of oral bioavailability of 100%. Striatal, in vivo microdialysis in conscious, freely-moving phenserine-treated rats demonstrated > 3-fold rise in brain ACh levels. Phenserine thus is rapidly absorbed and cleared from the body, but produces a long-lasting stimulation of brain cholinergic function at well tolerated doses and hence has superior properties as a drug candidate for AD. It selectively inhibits AChE, minimizing potential BChE side effects. Its long duration of action, coupled with its short pharmacokinetic half-life, reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/farmacocinética , Fisostigmina/farmacología , Fisostigmina/farmacocinética , Administración Oral , Enfermedad de Alzheimer/patología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Inhibidores de la Colinesterasa/administración & dosificación , Modelos Animales de Enfermedad , Semivida , Infusiones Intravenosas , Masculino , Fisostigmina/administración & dosificación , Fisostigmina/análogos & derivados , Ratas , Ratas Endogámicas F344 , Tacrina/administración & dosificación , Tacrina/farmacocinética , Tacrina/farmacología
4.
FEBS Lett ; 229(1): 82-6, 1988 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-3345841

RESUMEN

Measuring ellipticities of (+/-)-colchicine and (+/-)-deacetamidocolchicine in the presence of tubulin afforded net positive CD bands with maxima at 340 nm resulting from reduction of the negative ellipticities upon binding of (-) enantiomers to the protein. Results of optical studies together with earlier NMR conformational analysis of these molecules substantiate the hypothesis that colchicinoids bind to tubulin with the phenyl-tropolone moiety in the 'aS' configuration. Natural colchicine which binds to tubulin, therefore, should be referred to as (-)-(aS,7S)-colchicine.


Asunto(s)
Colchicina/metabolismo , Tubulina (Proteína)/metabolismo , Animales , Bovinos , Dicroismo Circular , Espectroscopía de Resonancia Magnética
5.
FEBS Lett ; 189(2): 225-30, 1985 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-3876242

RESUMEN

[3H]MPP+ had lower Km and higher Vmax values for its accumulation in rat brain synaptosomes than did [3H]MPTP. The kinetic parameters favored the uptake of [3H]MPP+ in the striatum to that in hypothalamus, whereas they were equally favorable for the uptake of [3H]MPTP in both regions. Hypothalamic uptake of [3H]MPTP and [3H]MPP+ was inhibited by desipramine, imipramine, norepinephrine, and serotonin. Striatal uptake of [3H]MPP+ and [3H]MPTP was blocked by nomifensine and dopamine. These results support the concept that MPTP accumulates in serotonergic neurons where it is oxidized by monoamine oxidase B to MPP+, which is released and then is selectively accumulated in dopaminergic neurons via the dopamine uptake system.


Asunto(s)
Dopamina/metabolismo , Piridinas/metabolismo , Compuestos de Piridinio/metabolismo , Serotonina/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , 1-Metil-4-fenilpiridinio , Animales , Cuerpo Estriado/metabolismo , Hipotálamo , Cinética , Norepinefrina/metabolismo , Ratas , Ratas Endogámicas , Sinaptosomas/metabolismo
6.
FEBS Lett ; 183(2): 345-8, 1985 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-3872811

RESUMEN

Chemical reactions of MPDP+, a recognized intermediate in the metabolic conversion of the neurotoxin MPTP by monoamine oxidase B into its major metabolite MPP+, were studied. Addition of cyanide to MPDP+ bromide in aqueous solutions afforded cyano-compound 5 which isomerized in the presence of silica gel into compound 6. Both 5 and 6 when heated yielded a third isomer 7. MPDP+ bromide disproportionated into MPTP and MPP+ in aqueous solution near neutral or slightly alkaline pH, a reaction which also occurred when MPDP+ bromide was treated with an amine in dichloromethane solution. Disproportionation of MPDP+ at physiological pH may be of biochemical significance, since formation of MPP+ from MPDP+ can occur non-enzymatically. MPTP, MPDP+, and MPP+ inhibited dopamine uptake in rat synaptosomal preparations with I50 values of 30, 37, and 3.4 microM, respectively. The competition of these compounds with dopamine for uptake sites in the membrane may contribute in part to the reduced levels of dopamine observed in animals treated with MPTP.


Asunto(s)
Piridinas/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Sitios de Unión , Bromuros , Fenómenos Químicos , Química , Cuerpo Estriado/metabolismo , Cianuros , Dopamina/metabolismo , Isomerismo , Monoaminooxidasa/metabolismo , Ratas , Sinaptosomas/metabolismo
7.
FEBS Lett ; 221(2): 325-6, 1987 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-3622772

RESUMEN

The S-configuration for (+)-primaquine prepared from the racemate by chemical resolution was established by solid-state X-ray analysis of the (+)-1-phenylethylurea obtained with R-(+)-1-phenylethylisocyanate.


Asunto(s)
Isocianatos , Primaquina , Cianatos , Conformación Molecular , Urea , Difracción de Rayos X
8.
FEBS Lett ; 234(1): 127-30, 1988 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-3391264

RESUMEN

Reaction of (-)-eseroline (1) with alkyl, aryl and aralkylisocyanates afforded a series of carbamate analogues of (-)-physostigmine (2) which were assayed for inhibition of acetyl- and butyrylcholinesterase (AChE and BChE, respectively) in vitro. Included in this study were two N-alkyl-substituted carbamates 9 and 14 obtained from (-)-eseroline (1) with dialkylcarbamoyl chlorides, and allophanates 12 and 13 obtained as by-products in the reaction of 1 and benzylcarbamoyl eseroline (8) with benzyl isocyanate. Whereas none of the analogues studied was more potent than 2 against electric eel AChE, and carbamates 6, 7 and 8 were all more than 3 times more potent against human plasma BChE than 2.


Asunto(s)
Carbamatos/farmacología , Inhibidores de la Colinesterasa , Fisostigmina/análogos & derivados , Acetilcolinesterasa , Animales , Butirilcolinesterasa/sangre , Fenómenos Químicos , Química , Electrophorus , Humanos , Indoles , Fisostigmina/farmacología
9.
FEBS Lett ; 201(2): 190-2, 1986 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-3709808

RESUMEN

Unnatural (+)-physostigmine (2) inhibited acetylcholinesterase (AChE) from electric eel considerably less than natural (-)-physostigmine (1), but 2 may because of its possible lower toxicity still be an interesting anticholinesterase agent. (-)-Eseroline (3), a major metabolite of (-)-physostigmine (1) and a potent narcotic analgetic, and its unnatural (+)-antipode (4), were both poor inhibitors of the enzyme. (-)-Dihydrosecophysostigmine (5), a ring-open analog of (-)-physostigmine was less, but (-)-N-methylphysostigmine (6) much more potent than the natural alkaloid. The availability of compounds related to (-)- and (+)-physostigmine by improved chemical synthesis suggests that further structural variation may well lead to other biologically interesting AChE inhibitors.


Asunto(s)
Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Fisostigmina/análogos & derivados , Animales , Anguilas/metabolismo , Indoles/farmacología , Fisostigmina/farmacología , Relación Estructura-Actividad
10.
FEBS Lett ; 199(1): 100-2, 1986 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-3485542

RESUMEN

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its deuterated analogues were oxidized to their corresponding dihydropyridinium species (MPDP+) by preparations of pure human liver MAO B:monoclonal antibody complex to investigate the mechanism of MPTP activation. Lineweaver-Burk plots of initial reaction rates revealed that the Km,app values for the various deuterated MPTP analogues were similar to those of MPTP. In contrast, Vmax,app values were substantially decreased by substitution of deuterium for hydrogen on the tetrahydropyridinium ring, especially at C-6. Deuterium substitution on the N-methyl group alone did not significantly reduce Vmax,app. These studies support the interpretation that oxidation of MPTP at the C-6 position on the tetrahydropyridine ring is a major rate-determining step in its biotransformation by MAO B.


Asunto(s)
Hígado/enzimología , Monoaminooxidasa/metabolismo , Piridinas/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Anticuerpos Monoclonales , Humanos , Cinética , Conformación Molecular , Monoaminooxidasa/inmunología , Especificidad por Sustrato
11.
FEBS Lett ; 163(2): 189-93, 1983 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-6315487

RESUMEN

The enantiomers of perhydrohistrionicotoxin were studied in their effects on endplate currents recorded at the junctional region of sartorius muscles of Rana pipiens. The two optical antipodes progressively decreased the peak amplitude of the endplate currents and were indistinguishable from each other at all times. The enantiomers shortened equally the time constants for endplate current decay, but did not alter their voltage sensitivities. Although perhydrohistrionicotoxin contains 4 chiral centers, complete steric inversion does not alter its effects on the acetylcholine receptor-ion channel complex. By contrast the recognition site of the AcChR is extremely sensitive to any change in the chirality of agonists.


Asunto(s)
Venenos de Anfibios/farmacología , Canales Iónicos/metabolismo , Unión Neuromuscular/efectos de los fármacos , Receptores Nicotínicos/efectos de los fármacos , Venenos de Anfibios/metabolismo , Animales , Electroquímica , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Placa Motora/efectos de los fármacos , Rana pipiens , Estereoisomerismo , Relación Estructura-Actividad
12.
FEBS Lett ; 186(2): 224-8, 1985 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-3874094

RESUMEN

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was oxidized to dihydropyridine MPDP+ and pyridine MPP+ by preparations of monoamine oxidase B (MAO B), including pure human liver MAO B:monoclonal antibody complex, Km,app values for MPTP and benzylamine, a preferred MAO B substrate, were 316 and 64 microM, respectively. 4-Phenyl-1,2,3,6-tetrahydropyridine (PTP), the nor derivative of MPTP, was also a substrate (Km,app = 221 microM). MPDP+, MPTP, and MPP+, but not PTP, were found to be irreversible inhibitors of MAO B. Our studies support the hypothesis that MPTP is oxidized in primate brain by MAO B to MPDP+, which is then converted to MPP+, a major metabolite found in the substantia nigra.


Asunto(s)
Isoenzimas/metabolismo , Hígado/enzimología , Monoaminooxidasa/metabolismo , Neurotoxinas/metabolismo , Piridinas/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Bovinos , Humanos , Isoenzimas/aislamiento & purificación , Cinética , Mitocondrias Hepáticas/enzimología , Monoaminooxidasa/aislamiento & purificación , Inhibidores de la Monoaminooxidasa
13.
FEBS Lett ; 223(1): 77-81, 1987 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-3666145

RESUMEN

Photooxidation of primaquine (1) and 5-hydroxyprimaquine (5) afforded a blue dye for which o-quinone structure 4 was elaborated. Similar oxidation of N-ethoxyacetylprimaquine (10) afforded o-quinone 11. Tissue schizontocidal activity of 4 and 11, and bisquinolylmethine 3 prepared earlier, showed that none of them had noteworthy antimalarial activity, but all three produced methemoglobin.


Asunto(s)
Primaquina , Animales , Biotransformación , Supervivencia Celular/efectos de los fármacos , Hemólisis , Hígado/efectos de los fármacos , Metahemoglobina , Oxidación-Reducción , Plasmodium/efectos de los fármacos , Primaquina/análogos & derivados , Primaquina/toxicidad , Relación Estructura-Actividad
14.
FEBS Lett ; 214(2): 291-4, 1987 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-3569526

RESUMEN

When the terminal amino group in the side chain of primaquine was blocked with an ethoxyacetyl group shown in 2, or eliminated by oxidative deamination to carboxylic acid 3, the antimalarial effect was markedly reduced in a screening assay which measures tissue schizonticidal activity. The optical isomers 1A and 1B of primaquine had similar antimalarial potency to the racemic mixture but 1B appeared less toxic. The 5-phenoxy-substituted analogue 4, belonging to a new class of antimalarials, showed similar potency in the assays to either 1A or 1B but seemed less cytotoxic than (+/-)-primaquine. Compounds 1A and 1B were found to be competitive inhibitors of human monoamine oxidase (MAO) A and B (Ki range 103-225 microM), but 4 showed 10-30-fold greater competitive inhibition of MAO A (Ki = 6.8 microM) and 40-90-fold greater non-competitive inhibition of MAO B (Ki = 2.3 microM).


Asunto(s)
Antimaláricos/farmacología , Malaria/tratamiento farmacológico , Inhibidores de la Monoaminooxidasa , Animales , Técnicas In Vitro , Plasmodium/efectos de los fármacos , Primaquina/análogos & derivados , Primaquina/farmacología , Estereoisomerismo , Relación Estructura-Actividad
15.
FEBS Lett ; 206(1): 125-9, 1986 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-3758343

RESUMEN

Standard samples of pure (+)-salutaridine and (-)-thebaine required to study the mammalian origin of morphine, were prepared from (+)-6-demethylsalutaridine by published procedures and were characterized by CD spectra and physical data. Reductive N-methylation of (-)-northebaine afforded (-)-thebaine, and when 13C-labeled formalin was used, (-)-thebaine with a 13C label on the N-methyl carbon atom resulted. The latter represents a model procedure to prepare ultimately N-14CH3-labeled (-)-thebaine and 14C-labeled congeners.


Asunto(s)
Morfinanos/metabolismo , Morfina/metabolismo , Tebaína/metabolismo , Animales , Fenómenos Químicos , Química , Dicroismo Circular , Metilación , Ratas
16.
FEBS Lett ; 262(1): 5-7, 1990 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-2318312

RESUMEN

The aS,7S-absolute configuration of (-)-colchicine (1) and (-)-N-acetylcolchinol methyl ether (3, NCME) suggested on the basis of 1H NMR data and negative Cotton effects at about 260 nm (EtOH) is firmly established by an X-ray analysis of urea 5, a compound derived from 3. Binding of these compounds to tubulin requires an aS-configuration of the biaryl system.


Asunto(s)
Colchicina , Conformación Molecular
17.
Neuropharmacology ; 32(2): 169-74, 1993 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-8383816

RESUMEN

Mescaline (3,4,5-trimethoxyphenylethylamine; MES) and its analogs, anhalinine (ANH) and methylenemescaline trimer (MMT) were investigated, using sciatic-sartorius preparations of the frog and cortical tissue from the rat. The effects of MES and its analogs were examined with respect to muscle twitch, resting membrane potential and nicotinic receptor binding. Mescaline and its analogs (10-100 microM) blocked both directly and neurally evoked twitches but their effects on neurally evoked twitches were greater than those on directly evoked twitches. Mescaline, ANH and MMT decreased amplitude of the miniature endplate and endplate potentials, decreased acetylcholine (ACh) quantal content, hyperpolarized the resting membrane potential and prolonged duration of the action potential. They did not significantly displace the binding of [125I]-alpha-bungarotoxin (alpha-BTX) to nicotinic receptors, at concentrations which blocked neuromuscular transmission. These results suggest that MES and its analogs inhibit cholinergic neuromuscular transmission by blocking release of ACh; they also affect K+ conductance.


Asunto(s)
Mescalina/farmacología , Unión Neuromuscular/efectos de los fármacos , Sistema Nervioso Parasimpático/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Acetilcolina/farmacología , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Estimulación Eléctrica , Técnicas In Vitro , Isoquinolinas/farmacología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Mescalina/análogos & derivados , Contracción Muscular/efectos de los fármacos , Músculos/citología , Músculos/efectos de los fármacos , Rana temporaria , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/efectos de los fármacos , Nervio Ciático/efectos de los fármacos , Relación Estructura-Actividad , Triazinas/farmacología
18.
Neuropharmacology ; 25(6): 583-6, 1986 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-3489197

RESUMEN

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenylpyridinium bromide (MPP+), 1-methyl-4-(3', 4'-dihydroxyphenyl)pyridinium bromide, 4-(3',4'-dihydroxyphenyl)pyridine, 4-phenyl-1,2,3,6-tetrahydropyridine and 4-(3',4'-dimethoxyphenyl)1,2,3,6-tetrahydropyridine were infused bilaterally into the substantia nigra of the rat (10 micrograms/24 hr for 4 days). The ability to inhibit spontaneous locomotor activity and to reduce levels of neurotransmitters and metabolites in the nigrostriatal system (striatum, substantia nigra) was compared with activity to inhibit dihydropteridine reductase (DHPR) in vitro. The compound MPP+ was most effective to reduce motor responding and to decrease levels of dopamine, DOPAC and HVA (50-56%) in the striatum in addition to reducing levels of dopamine, DOPAC, noradrenaline, serotonin and 5-HIAA (42-86%) in the substantia nigra, yet MPP+ has been shown to have very weak ability to inhibit DHPR. In contrast, 4-(3',4'-dihydroxyphenyl)pyridine and 1-methyl-4-(3',4'-dihydroxyphenyl)pyridinium bromide were in the order of 10(4) and 2 X 10(5) times, respectively, more potent than MPP+ to inhibit DHPR in vitro, but these compounds failed to modify dopamine neuronal function when assessed in vivo. Therefore, there would not appear to be any correlation between the ability to modify dopamine neuronal function, as assessed behaviourally or biochemically, and ability to inhibit DHPR in synaptosomes from the striatum of the rat in vitro.


Asunto(s)
Actividad Motora/efectos de los fármacos , Piridinas/farmacología , Sustancia Negra/fisiología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Masculino , Piridinas/administración & dosificación , Ratas , Ratas Endogámicas , Relación Estructura-Actividad , Sustancia Negra/efectos de los fármacos
19.
J Med Chem ; 27(12): 1729-33, 1984 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-6094813

RESUMEN

Spin probes of deacetylcholchicine (1), 4-(hydroxymethyl)colchicine (2), and colchifoline (3) have been synthesized to study the binding site for colchicine on tubulin. Acylation of 1-3 with (+/-)-2,2,5,5-tetramethyl-1-pyrrolidinyloxy-3-carboxylic acid (4) afforded diastereomeric mixtures of the esters 5-8 and the amides 9 and 10. Pure diastereomers of 3 were synthesized with 4a and 4b, which inhibited the binding of colchicine by 60%. In the presence of calf brain microtubular protein, the colchifoline spin labels underwent reduction of the nitroxide group, which precluded their use to study the topography of the colchicine binding site.


Asunto(s)
Colchicina/análogos & derivados , Colchicina/farmacología , Marcadores de Spin/síntesis química , Tubulina (Proteína)/metabolismo , Animales , Unión Competitiva , Encéfalo/metabolismo , Colchicina/síntesis química , Colchicina/metabolismo , Espectroscopía de Resonancia por Spin del Electrón , Indicadores y Reactivos , Espectrometría de Masas , Microtúbulos/metabolismo , Unión Proteica , Ratas , Estereoisomerismo , Relación Estructura-Actividad
20.
J Med Chem ; 28(3): 311-7, 1985 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-3871859

RESUMEN

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a nigrostriatal neurotoxin which can cause irreversible parkinsonism in humans and primates by selective destruction of neurons in the substantia nigra. It is possible that MPTP could be metabolized by hydroxylation of the phenyl ring and/or aromatization of its nitrogen-containing ring. Hydroxylated derivatives of 4-phenyl-1,2,3,6-tetrahydropyridine, 4-phenylpiperidine, and 4-phenylpyridine were synthesized and tested in vitro as inhibitors of dihydropteridine reductase (DHPR) from human liver and rat striatal synaptosomes. It was found that all hydroxy derivatives were about 100-10 000 times more inhibitory than MPTP to DHPR. The inhibitory potency of the hydroxylated derivatives increased with the number of hydroxyl substitutions present on the phenyl ring (catechol greater than phenol) and with oxidation of the nitrogen-containing ring (pyridine greater than tetrahydropyridine greater than piperidine).


Asunto(s)
Dihidropteridina Reductasa/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , Piridinas/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Humanos , Hidroxilación , Piridinas/farmacología , Relación Estructura-Actividad
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