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J B Fischer

Publications and source records attributed to J B Fischer.

At least 19 recordsLinked to original sources
PubMed1997

Synthesis and pharmacological evaluation of N-(2,5-disubstituted phenyl)-N'-(3-substituted phenyl)-N'-methylguanidines as N-methyl-D-aspartate receptor ion-channel blockers.

In the mammalian central nervous system, the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors may play an important role in brain diseases such as stroke, brain or spinal cord trauma, epilepsy, and certain neurodegenerative diseases. Compounds which specifically antagonize the actions of the neurotransmitter glutamate at the NMDA receptor ion-channel site offer a novel approach to treating these disorders. CERESTAT (4, aptiganel CNS 1102) is currently undergoing clinical trial for the treatment of traumatic brain injury and stroke. Previously, we reported that analogues of N-1-naphthyl-N'-(3-ethylphenyl)-N'-methylguanidine (4) bound to the NMDA receptor ion-channel site with high potency and selectivity. Recently, molecules active at both sigma receptors and NMDA receptor sites were investigated. A series of substituted diphenylguanidines 6 which are structurally related to N-1-naphthyl-N'-(3-ethylphenyl)-N'-methylguanidine was prepared. Compounds containing appropriate substitution pattern in one of the phenyl rings of diphenylguanidines displayed high affinity. For example, N-(2,5-dibromophenyl)-N'-(3-ethylphenyl)-N'- methylguanidine (27b, R2 = R5 = Br, R3 = C2H5) exhibited potency at both sigma receptors and NMDA receptor sites; 27b also showed high efficacy in vivo in a neonatal rat excitotoxicity model. Further studies indicated that substituent effects were important in this compound series, and 2,5-disubstituted phenyl was the preferred substitution pattern for high-affinity binding at NMDA receptor sites. Bromo and methylthio were the optimal substituents for the R2 and R5 positions of the 2,5-disubstituted phenyl group, respectively. N-(2-Bromo-5-(methylthio)phenyl)-N'- (3-ethylphenyl)-N'-methylguanidine (34b, R2 = Br, R5 = SMe, R3 = C2H5) was highly active at NMDA receptor sites. We found that the binding affinity of guanidines of type 6 could be further enhanced with the appropriate substitution at R3. Optimal activity in this series are afforded by 43b and 44b (R2 = Cl or Br, R5 = R3 = SCH3). Both 43b and 44b bound to NMDA receptor sites with high potency and selectivity (Ki vs [3H]MK-801: 1.87 and 1.65 nM, respectively); these compounds are active in vivo in various animal models of neuroprotection. The structure--activity relationships for these compounds at the NMDA receptor ion-channel site are discussed.

Animals↗
PubMed1997

Psychosocial consequences of bone marrow transplantation in donor and nondonor siblings.

We investigated the psychosocial effects of bone marrow transplantation (BMT) on siblings of transplant recipients. We asked how donor siblings compared with nondonor siblings on quantitative measures of behavior, psychological distress, and sense of self. Participants included 44 siblings (21 donors and 23 nondonors, ages 6-18 yr) of surviving pediatric BMT patients. On self-report measures, donors reported significantly more anxiety and lower self-esteem than nondonors. On teacher-rated scales, donors showed significantly more adaptive skills in school. On these same scales, nondonors showed significantly more school problems than donors. One-third of the siblings in each group reported a moderate level of post-traumatic stress reaction. Exploratory multiple regression analyses point to factors that might influence sibling adjustment and suggest counseling strategies and avenues for future research.

Adaptation, Psychological↗
PubMed1995

Neuroprotective use-dependent blockers of Na+ and Ca2+ channels controlling presynaptic release of glutamate.

We have originated a family of N,N'-disubstituted guanidines that block the voltage-activated Ca2+ and Na+ channels governing glutamate release. These compounds, CNS 1237 (N-acenaphthyl-N'-methoxynaphthyl guanidine) and its analogues, are "use dependent" in their ability to attenaute neurotransmitter release: they block glutamate release with greater efficacy under conditions of persistent or repetitive depolarization, as would be encountered under pathophysiological circumstances, relative to their ability to block glutamate release elicited by brief, transient depolarizations more characteristic of normal physiological release events in nonischemic brain. Using electrophysiological and rapid kinetic methods, we have differentiated the use-dependent block of the relevant Na+ and Ca2+ channels governing neurotransmitter release from the mechanism of channel antagonism exhibited by, respectively, the substituted guanidine Na+ channel blocker tetrodotoxin (TTX) and venom peptide Ca2+ antagonists. To characterize use-dependent Na+ channel block by CNS 1237, we have employed whole-cell voltage-clamp recordings from a Chinese hamster ovary (CHO) cell line expressing cloned mammalian type II Na+ channels. These experiments demonstrated that, in contrast to the actions of TTX under the same conditions, the potency of Na+ channel block by CNS 1237 is greatly enhanced by depolarizing stimuli in a frequency-dependent manner. Ca2+ channel-activated glutamate release from brain nerve terminal preparations was measured with approximately 300 msec time resolution over a 5-second period of high K(+)-depolarization, using a rapid superfusion technique. CNS 1237 and analogues, at 1-3 microM, accelerated the decay of glutamate release by 40-70%, reflecting depolarization-induced enhancement of block. In contrast, blockade of glutamate release by the Ca2+ channel antagonist peptide toxins omega-aga IV-A (from spider venom) and omega-conotoxin M-VII-C (from cone snail venom) exhibited "reverse-use-dependence:" at concentrations of 0.3 microM, which blocked the initial amplitude of glutamate release by 40-60%, the decay time constant for glutamate release was significantly increased, indicating depolarization-induced relief of block. These findings establish that CNS 1237 and other members of this compound series are use-dependent blockers of the voltage-activated ion channels governing glutamate release. Studies of CNS 1237 in the rat middle cerebral artery occlusion (MCAO) focal stroke model have indicated infarct size reduction comparable to that observed by the same investigators for the glutamate release blocker (BW 619C89 (Burroughs-Wellcome, now in clinical development). Maximal infarct size reduction is achieved with a 3-mg/kg bolus followed by a 4-hour infusion of 0.75 mg/kg/hr.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Structural features important for sigma 1 receptor binding.

Two problems that have hampered sigma receptor research are (i) a lack of high-affinity agents and (ii) the recent identification of multiple populations of sigma receptors (i.e., sigma 1 and sigma 2 sites). Recently, several high-affinity sigma ligands have been identified, and the term superpotent sigma ligands has been coined to describe agents with Ki values of < 1 nM. We have previously shown that appropriately N-substituted phenylalkylamines bind at sigma receptors with high affinity. In the present investigation, we examine the structure-affinity relationships of these phenylalkylamine derivatives for sigma 1 binding and describe some of the first superpotent sigma 1 ligands. A binding model was developed to account for the structural features of the phenylalkylamines that appear to be important for the interaction of these agents with sigma 1 sites.

Alkylation↗
PubMed1994

Synthesis and structure-activity studies of N,N'-diarylguanidine derivatives. N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine: a new, selective noncompetitive NMDA receptor antagonist.

Diarylguanidines, acting as NMDA receptor ion channel site ligands, represent a new class of potential neuroprotective drugs. Several diarylguanidines structurally related to N,N'-di-o-tolylguanidine (DTG), a known selective sigma receptor ligand, were synthesized and evaluated in in vitro radioligand displacement assays, with rat or guinea pig brain membrane homogenates, using the NMDA receptor ion channel site specific radioligand [3H]-(+)-5(S)-methyl-10(R),11-dihydro-5H-dibenzo[a,d]cyclohepten-5 ,10- imine (MK-801, 3), and the sigma receptor-specific radioligand [3H]-di-o-tolylguanidine (DTG, 5). This paper presents the structure-activity relationships leading to novel tri- and tetrasubstituted guanidines, which exhibit high selectivity for NMDA receptor ion channel sites and weak or negligible affinity for sigma receptors. The in vitro binding results from symmetrically substituted diphenylguanidines indicated that compounds having ortho or meta substituents (with respect to the position of the guanidine nitrogen) on the phenyl rings showed greater affinity for the NMDA receptor ion channel site compared with para-substituted derivatives. Among the group of ring substituents studied for symmetrical diarylguanidines, an isopropyl group was preferred at the ortho position and an ethyl group was preferred at the meta position. Several unsymmetrical guanidines containing a naphthalene ring on one nitrogen atom and an ortho- or a meta-substituted phenyl ring on the second nitrogen atom, e.g., N-1-naphthyl-N'-(3-ethylphenyl)guanidine (36), showed a 3-5-fold increase in affinity for the NMDA receptor ion channel site and no change in sigma receptor affinity compared to the respective symmetrical counterparts. Additional small substituents on the guanidine nitrogen atoms bearing the aryl rings resulted in tri- and tetrasubstituted guanidine derivatives which retained affinity for NMDA receptor ion channel sites but exhibited a significant reduction in their affinities for sigma receptors. For example, N-1-naphthyl-N'-(3-ethylphenyl)-N'-methylguanidine (40) showed high affinity for the NMDA receptor ion channel site (IC50 = 36 nM vs [3H]-3) and low affinity for sigma receptors (IC50 = 2540 nM vs [3H]-5). Selectivity for the NMDA receptor ion channel sites over sigma receptors appears to be dependent upon the structure of the additional substituents on the guanidine nitrogen atoms bearing the aryl groups. Methyl and ethyl substituents are most preferred in the tri- and tetrasubstituted diarylguanidines. The trisubstituted guanidine, N-1-naphthyl-N'-(3-ethylphenyl)-N'-methylguanidine (40) and its close analogues showed good in vivo neuroprotection and are potential neuroprotective drug candidates for the treatment of stroke and other neurodegenerative disorders.

Animals↗
PubMed1994

In vitro neuroprotection by substituted guanidines with varying affinities for the N-methyl-D-aspartate receptor ionophore and for sigma sites.

Radioligand binding techniques were used to determine the affinity of a series of substituted guanidine derivatives for 1) the binding site within the ion channel of the N-methyl-D-aspartate (NMDA) receptor, as defined by displacement of MK-801 ([3H]dizocilpine) and 2) sigma sites as defined by displacement of [3H]N,N'-di-(o-tolyl)guanidine. The goal was to find ligands with high affinity and selectivity for the NMDA receptor ion-channel site. The neuroprotective activity of these compounds was assessed by their ability to protect cortical neurons from injury caused by a 5-min exposure to 500 microM glutamate in vitro. Release of lactate dehydrogenase into the culture medium by damaged neurons was used as an index of neuronal injury. The 14 compounds tested had IC50 values ranging from 37.3 nM to 12.7 microM for the NMDA receptor ion-channel site and from 8.3 nM to 7.25 microM for sigma sites. Affinity for the ion-channel site was improved by unsymmetrical substitutions on the guanidine moiety. All compounds in the series protected cortical neurons against glutamate toxicity, with EC50 values (concentration affording 50% protection) ranging from 0.38 to 28.25 microM. The neuroprotective effect of each compound was positively correlated with its ion-channel site affinity (r = 0.94); no correlation between neuroprotective efficacy and sigma site binding affinity was found (r V -0.13) establishing clearly that neuroprotection in this assay was linked to NMDA antagonist properties.

Animals↗
PubMed1992

New CNS-specific calcium antagonists.

Ischemic insults to the brain in stroke or traumatic brain injury produce excessive release of glutamate from depolarized nerve terminals. This excessive glutamate release in turn stimulates massive calcium entry into nerve cells, activating a biochemical cascade that results in cell death. A major pathway of calcium entry into depolarized nerve cells is through voltage-sensitive, high threshold calcium channels. A large fraction of this calcium entry is mediated through "R-type" calcium channels, channels resistant to blockage by dihydropyridine calcium antagonists such as nimodipine. A newly discovered compound derived from spider venom, CNS 2103, antagonizes both R-type channels and dihydropyridine-sensitive ("L-type") calcium channels. This broad spectrum of action, coupled with selectivity for calcium channels over other classes of voltage-sensitive and ligand-gated ion channels, makes CNS 2103 an interesting lead for development of drugs to treat ischemic brain injury. Activation of presynaptic ("N-type") calcium channels in nerve terminals is a primary cause of excessive neurotransmitter release in brain ischemia. Prevention of glutamate release by blockade of N-type channels in glutamatergic nerve terminals may, at an early stage in the pathophysiological cascade, abort the process leading to nerve cell death. Cambridge NeuroScience has developed a novel rapid kinetic approach for monitoring glutamate release from brain nerve terminals in vitro, and this has led to CNS 1145, a substituted guanidine that selectively blocks a kinetic component of calcium-dependent glutamate release mediated by persistent depolarization. Additional evidence suggests that CNS 1145 antagonizes presynaptic N-type calcium channels, and this may account at least in part for its ability to block glutamate release.

Animals↗
PubMed1991

Identification and exploitation of the sigma-opiate pharmacophore.

Certain benzomorphan "sigma-opiates" such as N-allylnormetazocine (NANM) bind at sigma receptors with modest affinity and with little selectivity (i.e., they also bind at phencyclidine or PCP sites). In order to identify the primary pharmacophore of the benzomorphans, we prepared several amine-substituted derivatives of 1-phenyl-2-aminopropane. Several simple alkyl-substituted analogues were shown to bind at sigma sites with affinities comparable to that of NANM itself; among these was the N-benzyl derivative 9 (Ki = 117 nM). Lengthening the spacer between the terminal amine and the phenyl group from one to five methylene units resulted in a significant increase in affinity (e.g. 15, Ki = 6.3 nM). In addition, unlike the benzomorphans, these phenalkylamines do not bind at PCP sites. The results of the present study reveal that (a) the 1-phenyl-2-aminopropane nucleus of the benzomorphans is sufficient for binding at sigma sites provided that the terminal amine is not a primary amine and that (b) introduction of (phenylalkyl)amine substituents affords compounds that represent a new class of high-affinity sigma-selective agents.

Animals↗
PubMed1991

Binding of substituted and conformationally restricted derivatives of N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane at sigma-receptors.

Certain benzomorphans, such as N-allylnormetazocine, are classical "sigma-opiates" that bind both at sigma and phencyclidine (PCP) binding sites with modest affinity. Recently, we identified N-substituted 2-phenylaminoethane as being the primary sigma-pharmacophore of the benzomorphans and demonstrated that 1-phenyl-2-aminopropane (2) derivatives, depending upon their terminal amine substituents, constitute a novel class of high-affinity sigma-selective agents. With this pharmacophore, it is shown in the present investigation that the aromatic hydroxyl group (a prime feature of all the sigma-opiates) contributes little to the binding of 2 at sigma-sites. It is also demonstrated that an N-substituted aminotetralin moiety (such as 17, a conformationally restricted analogue of 2) may also be considered a sigma-opiate pharmacophore. Unlike the sigma-opiates, derivatives of 2 and 17 display no affinity for PCP sites and must consequently lack those structural features important for the binding of benzomorphans at PCP sites. Because 3-phenylpiperidines and related sigma-ligands also possess a phenylalkylamine imbedded within their structures, we propose that the 2-phenylaminoethane moiety is a common sigma-pharmacophore for derivatives of 2, the 3-phenylpiperidines, and the sigma-opiates.

Animals↗
PubMed1991

Novel 1-phenylpiperazine and 4-phenylpiperidine derivatives as high-affinity sigma ligands.

sigma receptors may represent an exciting new approach for the development of novel psychotherapeutic agents. Unfortunately, many of the commonly used sigma ligands lack selectivity (e.g., many bind at phencyclidine or dopamine receptors) or suffer from other serious drawbacks. Recently, we described a series of 2-phenylaminoethanes that bind at sigma receptors with high affinity and selectivity. Because there is evidence that 1-phenylpiperazines can structurally mimic the 2-phenylaminoethane moiety, we prepared a series of 1-phenylpiperazines and related analogues and incorporated structural features already shown to enhance the sigma binding of the 2-phenylaminoethanes. Several of these derivatives bind at sigma receptors with high affinity (Ki = 1-10 nM) and lack appreciable affinity for phencyclidine and dopamine receptors. In as much as certain of these agents structurally resemble the high-affinity, but nonselective, sigma ligand haloperidol, and because they bind with 10 times the affinity of haloperidol, we have apparently identified what appears to be the primary sigma pharmacophore of that agent.

Animals↗
PubMed1990

Synthesis and structure-activity relationships of N,N'-di-o-tolylguanidine analogues, high-affinity ligands for the haloperidol-sensitive sigma receptor.

With an eye toward the development of novel atypical antipsychotic agents, we have studied the structure-affinity relationships of N,N'-di-o-tolylguanidine (DTG, 3) and its congeners at the haloperidol-sensitive sigma receptor. A number of DTG analogues were synthesized and evaluated in in vitro radioligand displacement experiments with guinea pig brain membrane homogenates, using the highly sigma-specific radioligands [3H]-3 and [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and the phencyclidine (PCP) receptor specific compounds [3H]-N-[1-(2-thienyl)-cyclohexyl]piperidine and [3H]-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10- imine. The affinity of N,N'-diarylguanidines for the sigma receptor decreases with increasing steric bulk of ortho substituents larger than C2H5. Hydrophobic substituents are generally preferred over similarly positioned hydrophilic ones. Furthermore, electroneutral substituents are preferred over strongly electron donating or withdrawing groups. Significant binding to the sigma receptor is usually retained as long as at least one side of the guanidine bears a preferred group (e.g. 2-CH3C6H5). Replacement of one or both aryl rings with certain saturated carbocycles (e.g. cyclohexyl, norbornyl, or adamantyl) leads to a significant increase in affinity. By combining the best aromatic and best saturated carbocyclic substituents in the same molecule, we arrived at some of the most potent sigma ligands described to date (e.g. N-exo-2-norbornyl-N'-(2-iodophenyl)guanidine, IC50 = 3 nM vs [3H]-3). All of the compounds tested were several orders of magnitude more potent at the sigma receptor than at the PCP receptor, with a few notable exceptions. This series of disubstituted guanidines may be of value in the development of potential antipsychotics and in the further pharmacological and biochemical characterization of the sigma receptor.

Animals↗
PubMed1989

Synthesis and characterization of a series of diarylguanidines that are noncompetitive N-methyl-D-aspartate receptor antagonists with neuroprotective properties.

Four diarylguanidine derivatives were synthesized. These compounds were found to displace, at submicromolar concentrations, 3H-labeled 1-[1-(2-thienyl)cyclohexyl]piperidine and (+)-[3H]MK-801 from phencyclidine receptors in brain membrane preparations. In electrophysiological experiments the diarylguanidines blocked N-methyl-D-aspartate (NMDA)-activated ion channels. These diarylguanidines also protected rat hippocampal neurons in vitro from glutamate-induced cell death. Our results show that some diarylguanidines are noncompetitive antagonists of NMDA receptor-mediated responses and have the neuroprotective property that is commonly associated with blockers of the NMDA receptor-gated cation channel. Diarylguanidines are structurally unrelated to known blockers of NMDA channels and, therefore, represent a new compound series for the development of neuroprotective agents with therapeutic value in patients suffering from stroke, from brain or spinal cord trauma, from hypoglycemia, and possibly from brain ischemia due to heart attack.

Animals↗
PubMed1989

Cloning of the cDNA and gene for a human D2 dopamine receptor.

A clone encoding a human D2 dopamine receptor was isolated from a pituitary cDNA library and sequenced. The deduced protein sequence is 96% identical with that of the cloned rat receptor with one major difference: the human receptor contains an additional 29 amino acids in its putative third cytoplasmic loop. Southern blotting demonstrated the presence of only one human D2 receptor gene. Two overlapping phage containing the gene were isolated and characterized. DNA sequence analysis of these clones showed that the coding sequence is interrupted by six introns and that the additional amino acids present in the human pituitary receptor are encoded by a single exon of 87 base pairs. The involvement of this sequence in alternative splicing and its biological significance are discussed.

Amino Acid Sequence↗
PubMed1988

The bombesin receptor is coupled to a guanine nucleotide-binding protein which is insensitive to pertussis and cholera toxins.

The neuropeptide bombesin acts on a variety of target cells to stimulate the processes of secretion and cell proliferation. In this study we determined whether bombesin receptors interact with known guanine nucleotide-binding proteins in four different cell types: GH4C1 pituitary cells, HIT pancreatic islet cells, Swiss 3T3 fibroblasts, and rat brain tissue. Maximal concentrations of nonhydrolyzable GTP analogs decreased agonist binding to bombesin receptors in membranes from all four sources. In GH4C1 and HIT cell membranes GTP analogs inhibited bombesin receptor binding with IC50 values of about 0.1 microM, whereas GDP analogs were approximately 10-fold less potent. In contrast, GMP and the nonhydrolyzable ATP analog adenylyl-imidodiphosphate had no effect at 100 microM. Equilibrium binding experiments in GH4C1 and HIT cell membranes indicated a single class of binding sites with a dissociation constant (Kd) for [125I-Tyr4]bombesin of 24.4 +/- 7.0 pM and a binding capacity of 176 +/- 15 fmol/mg protein. Guanine nucleotides decreased the apparent affinity of the receptors without significantly changing receptor number. Consistent with this observation, guanine nucleotides also increased the rate of ligand dissociation. Pretreatment of GH4C1 or HIT cells with either pertussis toxin (100 ng/ml) or cholera toxin (500 ng/ml) for 18 h did not affect agonist binding to membrane bombesin receptors, its regulation by guanine nucleotides, or bombesin stimulation of hormone release. Although pertussis toxin pretreatment has been reported to block bombesin stimulation of DNA synthesis in Swiss 3T3 cells, it did not alter the binding properties of bombesin receptors in Swiss 3T3 membranes or inhibit the rapid increase in intracellular [Ca2+] produced by bombesin in these cells. In summary, our results indicate that the bombesin receptor interacts with a guanine nucleotide-binding protein which exhibits a different toxin sensitivity from those which regulate adenylate cyclase as well as those which couple some receptors to phospholipases.

Adenylate Cyclase Toxin↗
PubMed1983

Release of norepinephrine from organ-cultured superior cervical ganglia: effects of the norepinephrine uptake inhibitor xylamine.

After preloading with [3H]norepinephrine (NE), organ-cultured superior cervical ganglia released increased amounts of [3H]NE when incubated with depolarizing K+ concentrations, tyramine or amphetamine. K+-induced release was Ca++-dependent, whereas tyramine- and amphetamine-induced release were not. Analysis of the released radioactivity by high-pressure liquid chromatography showed that these releasing stimuli caused primarily an increase in NE release, with little increase in the release of NE metabolites. Incubation with 10 microM xylamine, an irreversible inhibitor of NE uptake, caused a small increase in [3H]NE efflux, but no reduction in the endogenous NE and dopamine levels in superior cervical ganglia. After xylamine treatment, tyramine-induced release was greatly inhibited, whereas release by amphetamine and K+ was not. The neuronal uptake inhibitor desipramine (1 microM), affected K+-, tyramine- and amphetamine-induced release in a manner similar to xylamine. It is concluded that xylamine is a very weak releasing agent in this tissue and that its effects on other release processes are consistent with its action as a NE uptake inhibitor. Amphetamine-induced release appears not to require the NE uptake system for either the uptake of amphetamine, as shown by the accumulation of [3H]amphetamine, or the efflux of NE.

Animals↗
PubMed1983

Xylamine, an irreversible inhibitor of norepinephrine uptake, is transported by this same uptake mechanism in cultured rat superior cervical ganglia.

The accumulation of tritium-labeled xylamine ([3H]XYL), an irreversible inhibitor of neuronal norepinephrine (NE) uptake, was studied in organ-cultured rat superior cervical ganglia (SCG). At concentrations below those which significantly inhibit NE uptake, [3H]XYL accumulation was linear with time for up to 2 hr; at higher concentrations, accumulation slowed within the first 10 min. [3H]XYL accumulation was inhibited by desipramine, cocaine, bretylium and by NE at concentrations similar to those required to inhibit NE uptake. Replacing Na+ with Li+ in the bathing medium also inhibited [3H]XYL accumulation by about 70%. After 2 days of organ culture, SCG [3H]XYL accumulation was increased in parallel with an increase in NE uptake. Reserpine pretreatment of SCG did not affect [3H]XYL accumulation. The hydrolysis product of XYL, xylaminol, was also accumulated by SCG, but its accumulation was not inhibited by desipramine or the absence at Na+. By using trichloroacetic acid precipitation followed by ethanol extractions, about 40% of the accumulated tritium appeared to be irreversibly bound to protein, whereas about 30% appeared to be bound to lipids. We conclude that XYL is accumulated in sympathetic neurons by the NE uptake system and that this accumulation may be necessary in order for XYL to produce its irreversible inhibition of NE uptake.

Animals↗