Brain Synaptic Membranes Research Articles

Validation of high-affinity binding sites for succinic acid through distinguishable binding of gamma-hydroxybutyric acid receptor-specific NCS 382 antipodes

Gamma-hydroxybutyric acid (GHB) binding to multiple sites for the tricarboxylic acid cycle intermediate succinic acid (SUC) has been disclosed recently. In order to better characterize these targets, distinguishable binding of GHB receptor-specific NCS 382 antipodes to [3H]-SUC or [3H]-GHB labelled sites in rat brain synaptic membranes was explored. Eutomer binding parameters suggest identity of the high-affinity target for SUC with a synaptic GHB receptor subtype.

Cyclothiazide binding to the GABAA receptor

In order to explore the molecular interaction between cyclothiazide (CTZ) and gamma-aminobutyric acidA (GABAA) receptors, possibly underlying inhibition of GABAA receptor currents, [3H]-CTZ was synthesized. Binding of [3H]-CTZ to rat brain synaptic membranes could be observed only in the presence of the GABAA receptor antagonist (-)[1S,9R]-bicuculline methiodide (BMI) (EC(50,BMI)=500+/-80microM). GABA decreased [(3)H]-CTZ binding induced by the presence 300microM and 3mM BMI with IC(50,GABA) values of 300+/-50microM and 5.0+/-0.7mM, respectively. Binding of CTZ to [3H]-CTZ labeled sites was characterized by IC(50,CTZ) values of 0.16+/-0.03muM ([BMI]=300microM) and 7.0+/-0.5microM ([BMI]=3mM). Binding of the diastereomeric fraction [3H]-(3R,1'S,4'S,5'R+3S,1'R,4'R,5'S)-CTZ induced by 3mM BMI was quantitatively the more significant in cerebrocortical and hippocampal membranes. It was characterized by IC(50,CTZ)=80+/-15nM and IC(50,GABA)=13+/-3mcapital EM, Cyrillic. In the absence of BMI, CTZ (1mM) significantly decreased GABA-induced enhancement of [3H]-flunitrazepam binding. Our findings suggest that functional inhibition may occur through binding of CTZ to an allosteric site of GABAA receptors. This allosteric site is possibly emerged in the receptor conformation, stabilized by BMI binding.

Synthesis and In-Vivo Evaluation of [11C]p-PVP-MEMA as a PET Radioligand for Imaging Nicotinic Receptors

Within the class of (4-pyridinyl)vinylpyridines developed by Abbott laboratories as potent neuronal nicotinic acetylcholine receptor ligands, p-PVP-MEMA ({(R)-2-[6-chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-3-yloxy]-1-methylethyl}methylamine) is the lead compound of a novel series that do not display the traditional nicotinic-like pyrrole-ring but still possessing high subnanomolar affinity (Ki 0.077 nm—displacement of [3H](–)cytisine from whole rat brain synaptic membranes). In the present study, p-PVP-MEMA and its nor-derivative ({(R)-2-[6-chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-3-yloxy]-1-methylethyl}methylamine) as precursor for labelling with the short-lived positron-emitter carbon-11 (T1/2 20.4 min) were synthesized in 10 chemical steps from 2-hydroxy-5-nitropyridine and Boc-d-alanine. N-Alkylation of nor-p-PVP-MEMA with [11C]methyl iodide afforded [11C]p-PVP-MEMA (>98% radiochemically pure, specific activity of 86.4 GBq μmol–1) in 2% (non-decay corrected and non-optimized) radiochemical yield, in 34 min (including HPLC purification and formulation). Preliminary positron emission tomography (PET) results obtained in a Papio hamadryas baboon showed that [11C]p-PVP-MEMA is not a suitable PET-radioligand.

Time-dependent inhibition of Na+/K+-ATPase induced by single and simultaneous exposure to lead and cadmium

Time-dependent interactions of Na+/K+-ATPase, isolated from rat brain synaptic plasma membranes (SPMs), with Cd2+ and Pb2+ ions in a single exposure and in a mixture were investigated in vitro. The interference of the enzyme with these metal ions was studied as a function of different protein concentrations and exposure time. The aim of the work was to investigate the possibility of selective recognition of Cd2+ and Pb2+ ions in a mixture, on the basis of the different rates of their protein-ligand interactions. Decreasing protein concentration increased the sensitivity of Na+/K+-ATPase toward both metals. The selectivity in protein-ligand interactions was obtained by variation of preincubation time (incubation before starting the enzymatic reaction).

Adenosine ecto-deaminase (ecto-ADA) from porcine cerebral cortex synaptic membrane

We have purified and investigated the role of adenosine ecto-deaminase (ecto-ADA) in porcine brain synaptic membranes and found a low activity of ecto-ADA in synaptic preparations from the cerebral cortex, hippocampus, striatum and medulla oblongata in the presence of purine transport inhibitors (NBTI, dipyridamole and papaverine). The purification procedure with affinity chromatography on epoxy–Toyopearl gel/purine riboside column as a crucial step of purification allowed a 214-fold purification of synaptic ecto-ADA with a yield of 30%. Gel filtration chromatography revealed a molecular mass estimated at 42.4 ± 3.9 kDa. The enzyme had a broad optimum pH and was not affected by mono- and divalent cations. Ecto-ADA revealed a low affinity to adenosine (Ado) and 2′-deoxyadenosine (2′-dAdo) ( K M = 286.30 ±40.38 μM and 287.14 ± 46.50 μM, respectively). We compared the affinity of ecto-ADA to the substrates with the physiological and pathological concentrations of the extracellular Ado in brains that do not exceed a low micromolar range even during ischemia and hypoxia, and with the affinity of adenosine receptors to Ado not exceeding a low nanomolar (A 1 and A 2A receptors) or low micromolar (A 2B and A 3) range. Taken together, our data suggest that the role of synaptic ecto-ADA in the regulation of the ecto-Ado level in the brain and in the termination of adenosine receptor signaling is questionable. The porcine brain synapses must have other mechanisms for the ecto-Ado removal from the synaptic cleft and synaptic ecto-ADA may also play an extra-enzymatic role in cell adhesion and non-enzymatic regulation of adenosine receptor activity.

The effects of endomorphins and diprotin A on striatal dopamine release induced by electrical stimulation—An in vitro superfusion study in rats

The endomorphins (EM1: Tyr-Pro-Trp-Phe-NH 2, and EM2: Tyr-Pro-Phe-Phe-NH 2) are recently discovered endogenous ligands for mu-opioid receptors (MORs) with role of neurotransmitters or neuromodulators in mammals. Cessation of their physiological action may be effected through rapid enzymatic degradation by the dipeptidyl-peptidase IV (DPPIV) found in the brain synaptic membranes. An in vitro superfusion system was utilized to investigate the actions of EM1, EM2 and specific DPPIV inhibitor diprotin A on the striatal release of dopamine (DA) induced by electrical stimulation in rats. The involvement of the different MORs (MOR1 and MOR2) in this process was studied by pretreatment with MOR antagonists β-funaltrexamine (a MOR1 and MOR2 antagonist) and naloxonazine (a MOR1 antagonist). EM1 significantly increased the tritium-labelled dopamine DA release induced by electrical stimulation. EM2 was effective only when the slices were pretreated with diprotin A. β-Funaltrexamine antagonized the stimulatory effects of both EM1 and EM2. The administration of naloxonazine did not appreciably influence the action of EM1, but blocked the action of EM2, at least when the slices were pretreated with diprotin A. These data suggest that both EM1 and EM2 increase DA release from the striatum and, though diprotin A does not affect the action of EM1, it inhibits the enzymatic degradation of EM2. The DA-stimulating action induced by EM1 seems to be mediated by MOR2, while that evoked by EM2 appears to be transmitted by MOR1.

Effect of neonatal hypothyroidism on Ca 2+-ATPase activity in the rat brain

Effect of neonatal hypothyroidism on kinetic properties of Ca 2+-ATPase from rat brain synaptic plasma membranes and microsomes were examined. Neonatal hypothyroidism resulted in significant decrease in the enzyme activity in both the membrane systems. The synaptic membranes in control group displayed presence of one kinetic component whereas a low affinity component became evident in the hypothyroid group. In the microsomes, both control as well as hypothyroid groups showed presence of two kinetic components with the latter group showing two-fold increase in the K m. The Ca 2+ binding characteristics were generally unaltered in the enzyme from both the membrane systems. Our results suggest that impairment in the Ca 2+-ATPase activity together with altered kinetic properties could be one of the underlying biochemical mechanisms leading to CNS dysfunction as a consequence of thyroid hormone deprivation during critical stages of brain development.

1167 PUBLICATION Adjuvant chemotherapy (CT) and patient compliance in non-small cell lung cancer (NSCLC). a multivariate analysis of 356 consecutively treated patients

Among over 60 polyamine derivatives tested, onlyN-(3-aminopropyl)octanediamine and bis-(3-aminopropyl)nonanediamine (TE393) markedly inhibited [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) binding at equilibrium in the presence of added spermidine (SPD) in “non-washed” rat brain synaptic membranes, without affecting that in the absence of added SPD. Although TE393 significantly potentiated [3H]MK-801 binding before equilibrium in the presence ofl-glutamic acid (Glu) alone or both Glu and glycine (Gly) added in “Triton-treated” membranes, the putative polyamine antagonists 1,10-decanediamine (DA10) and arcaine invariably inhibited binding irrespective of the addition of agonists. In the absence of added SPD, in addition, TE393 markedly enhanced abilities of both Glu and Gly to potentiate [3H]MK-801 binding before equilibrium. However, TE393 induced a rightward shift of the concentration-response curve of SPD for [3H]MK-801 binding before equilibrium. Moreover, TE393 was effective in potentiating binding of an antagonist but not an agonist radioligand to the NMDA domain and in inhibiting binding of an antagonist but not an agonist radioligand to the Gly domain. The potentiation of NMDA antagonist binding by TE393 occurred in a manner sensitive to prevention by arcaine but not by DA10. These results suggest that TE393 may be a novel ligand at the polyamine domain with an ability to interact with both the NMDA and Gly recognition domains in antagonist-preferring forms.

1165 PUBLICATION Second-line treatment with pemetrexed following platinum based doublet chemotherapy in Malignant Pleural Mesothelioma

Among over 60 polyamine derivatives tested, onlyN-(3-aminopropyl)octanediamine and bis-(3-aminopropyl)nonanediamine (TE393) markedly inhibited [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) binding at equilibrium in the presence of added spermidine (SPD) in “non-washed” rat brain synaptic membranes, without affecting that in the absence of added SPD. Although TE393 significantly potentiated [3H]MK-801 binding before equilibrium in the presence ofl-glutamic acid (Glu) alone or both Glu and glycine (Gly) added in “Triton-treated” membranes, the putative polyamine antagonists 1,10-decanediamine (DA10) and arcaine invariably inhibited binding irrespective of the addition of agonists. In the absence of added SPD, in addition, TE393 markedly enhanced abilities of both Glu and Gly to potentiate [3H]MK-801 binding before equilibrium. However, TE393 induced a rightward shift of the concentration-response curve of SPD for [3H]MK-801 binding before equilibrium. Moreover, TE393 was effective in potentiating binding of an antagonist but not an agonist radioligand to the NMDA domain and in inhibiting binding of an antagonist but not an agonist radioligand to the Gly domain. The potentiation of NMDA antagonist binding by TE393 occurred in a manner sensitive to prevention by arcaine but not by DA10. These results suggest that TE393 may be a novel ligand at the polyamine domain with an ability to interact with both the NMDA and Gly recognition domains in antagonist-preferring forms.

Inhibition of Transient Lower Esophageal Sphincter Relaxation and Gastroesophageal Reflux by Metabotropic Glutamate Receptor Ligands

Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism of gastroesophageal acid reflux. TLESR is mediated via vagal pathways, which may be modulated by metabotropic glutamate receptors (mGluRs). Group I mGluRs (mGluR1 and 5) have excitatory effects on neurons, whereas group II (mGluR2 and 3) and group III (mGluR4, 6, 7, and 8) are inhibitory. This study determined the effect of mGluRs on triggering of TLESR and reflux in an established conscious ferret model. Esophageal manometric/pH studies were performed in ferrets with chronic esophagostomies. TLESR were induced by a gastric load of 25 mL glucose (pH 3.5) and 30 mL air. In control treated animals, gastric load induced 3.52 +/- 0.46 TLESRs per 47-minute study, 89.7% of which were associated with reflux episodes (n = 16). The mGluR5 antagonist MPEP inhibited TLESR dose dependently, with maximal 71% +/- 7% inhibition at 35 micromol/kg (n = 9; P < .0001). MPEP also significantly reduced reflux episodes (P < .001) and increased basal lower esophageal sphincter pressure (P < .05). MPEP inhibited swallowing dose dependently, suggesting a common action on trigger mechanisms for swallowing and TLESR. The more selective analogue, MTEP, had more potent effects (90% +/- 6% inhibition TLESR at 40 micromol/kg; n = 8; P < .0001). In contrast, the group I agonist DHPG tended to increase TLESR. The group II agonist (2R, 4R)-APDC was ineffective, whereas the group III agonist L-(AP4 slightly reduced TLESR (33% at 11 micromol/kg; P < .05). The selective mGluR8 agonist (S)-3, 4-DCPG inhibited TLESR by 54% at 15 micromol/kg (P < .01). mGluR5 antagonists potently inhibit TLESR and reflux in ferrets, implicating mGluR5 in the mechanism of TLESR. mGluR5 antagonists are therefore promising as therapy for patients with GERD.

Association of an A-Kinase-anchoring Protein Signaling Scaffold with Cadherin Adhesion Molecules in Neurons and Epithelial Cells

A-kinase-anchoring protein (AKAP) 79/150 organizes a scaffold of cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and protein phosphatase 2B/calcineurin that regulates phosphorylation pathways underlying neuronal long-term potentiation and long-term depression (LTD) synaptic plasticity. AKAP79/150 postsynaptic targeting requires three N-terminal basic domains that bind F-actin and acidic phospholipids. Here, we report a novel interaction of these domains with cadherin adhesion molecules that are linked to actin through beta-catenin (beta-cat) at neuronal synapses and epithelial adherens junctions. Mapping the AKAP binding site in cadherins identified overlap with beta-cat binding; however, no competition between AKAP and beta-cat binding to cadherins was detected in vitro. Accordingly, AKAP79/150 exhibited polarized localization with beta-cat and cadherins in epithelial cell lateral membranes, and beta-cat was present in AKAP-cadherin complexes isolated from epithelial cells, cultured neurons, and rat brain synaptic membranes. Inhibition of epithelial cell cadherin adhesion and actin polymerization redistributed intact AKAP-cadherin complexes from lateral membranes to intracellular compartments. In contrast, stimulation of neuronal pathways implicated in LTD that depolymerize postsynaptic F-actin disrupted AKAP-cadherin interactions and resulted in loss of the AKAP, but not cadherins, from synapses. This neuronal regulation of AKAP79/150 targeting to cadherins may be important in functional and structural synaptic modifications underlying plasticity.

Development of a New Analgesic Based on Metabolism of Endomorphin, an Endogenous Opioid Peptide

AbstractFor Abstract see ChemInform Abstract in Full Text.

Development of a new analgesic based on metabolism of endomorphin, an endogenous opioid peptide

Endomorphin-2 (Tyr-Pro-Phe-PheNH(2)) was discovered as an endogenous ligand for the mu-opioid receptor. The physiologic function of endomorphin-2 as a neurotransmitter or neuromodulator may cease after rapid enzymatic processing in the synapses of the brain, like other neuropeptides. The present study was conducted to examine the metabolism of endomorphin-2 by synaptic membranes prepared from mouse brain. Major metabolites were free tyrosine, free phenylalanine, Tyr-Pro, and PheNH(2). Both the degradation of endomorphin-2 and the accumulation of major metabolites were inhibited by specific inhibitors of dipeptidyl peptidase IV, such as diprotin A and B. On the other hand, the accumulation of Phe-PheNH(2) and Pro-Phe-PheNH(2) was increased in the presence of bestatin, an aminopeptidase inhibitor, whereas that of free phenylalanine and PheNH(2) was decreased. Furthermore, purified dipeptidyl peptidase IV hydrolyzed endomorphin-2 at the cleavage site, the Pro(2)-Phe(3) bond. Thus degradation of endomorphin-2 by brain synaptic membranes appears to occur mainly through the cleavage of the Pro(2)-Phe(3) bond by dipeptidyl peptidase IV, followed by the release of free phenylalanine and PheNH(2) from the liberated fragment, Phe-PheNH(2), by aminopeptidase. We have also examined the effects of diprotin A on the antinociception induced by intracerebroventricularly administered endomorphin-2 in the mouse paw withdrawal test. Diprotin A simultaneously injected with endomorphin-2 enhanced endomorphin-2-induced antinociception. These results indicate that dipeptidyl peptidase IV may be an important peptidase responsible for terminating endomorphin-2-induced antinociception at the supraspinal level in mice. These findings also suggest that selective dipeptidyl peptidase IV inhibitors or dipeptidyl peptidase IV-resistant endomorphin-2 analogues have the potential for the clinical use as analgesics.

Caveolin-1 Interacts with 5-HT2A Serotonin Receptors and Profoundly Modulates the Signaling of Selected Gαq-coupled Protein Receptors

5-Hydroxytryptamine 2A (5-HT(2A)) serotonin receptors are important for a variety of functions including vascular smooth muscle contraction, platelet aggregation, and the modulation of perception, cognition, and emotion. In a search for 5-HT(2A) receptor-interacting proteins, we discovered that caveolin-1 (Cav-1), a scaffolding protein enriched in caveolae, complexes with 5-HT(2A) receptors in a number of cell types including C6 glioma cells, transfected HEK-293 cells, and rat brain synaptic membrane preparations. To address the functional significance of this interaction, we performed RNA interference-mediated knockdown of Cav-1 in C6 glioma cells, a cell type that endogenously expresses both 5-HT(2A) receptors and Cav-1. We discovered that the in vitro knockdown of Cav-1 in C6 glioma cells nearly abolished 5-HT(2A) receptor-mediated signal transduction as measured by calcium flux assays. RNA interference-mediated knockdown of Cav-1 also greatly attenuated endogenous Galpha(q)-coupled P2Y purinergic receptor-mediated signaling without altering the signaling of PAR-1 thrombin receptors. Cav-1 appeared to modulate 5-HT(2A) signaling by facilitating the interaction of 5-HT(2A) receptors with Galpha(q). These studies provide compelling evidence for a prominent role of Cav-1 in regulating the functional activity of not only 5-HT(2A) serotonin receptors but also selected Galpha(q)-coupled receptors.

Molecular interaction of NMDA receptor subunit NR3A with protein phosphatase 2A.

The catalytic subunit of the serine-threonine protein phosphatase 2A (PP2A) was previously found to bind to the carboxyl domain of NMDA receptor (NMDAR) subunit NR3A. We now report that NR3A constitutively associates with the PP2A holoenzyme, but not the core enzyme in rat brain synaptic plasma membranes. We also identified critical amino acids in NR3A required for binding to PP2A. We performed alanine-scanning mutagenesis in the PP2A-binding domain of the NR3A C-terminal (NR3Ac), then co-expressed the mutants together with the PP2A catalytic subunit in a yeast two-hybrid system and human embryonic kidney (HEK) 293 cells. We found that mutation of leucine 958, leucine 973 or histidine 974 or deletion of a spacer sequence of more than six amino acids between leucine 958 and histidine 974 disrupted the NR3A/PP2A interaction.

Molecular Cloning of a Sixth Member of the K+-dependent Na+/Ca2+ Exchanger Gene Family, NCKX6

Bioinformatic and molecular cloning tools were used to identify and isolate cDNA clones from mouse and human tissues that encode the sixth member of the K(+)-dependent Na+/Ca2+ exchanger family, NCKX6. The mouse NCKX6 protein is 585 amino acids long and shares about 62% sequence similarity with previously identified exchangers in the alpha-repeat regions but has little primary sequence similarity outside these regions. NCKX6 transcripts of 4 kb are abundantly expressed in all tissues examined and are thus more broadly distributed than previously described NC(K)X family members. Two alternatively spliced products of this novel gene were identified that encode proteins of different length. The short isoform differs from the full-length isoform at the C-terminal hydrophobic domain as a result of a shift in the reading frame caused by the deletion of two exons. Both NCKX6 isoforms were expressed in HEK-293 cells. Functional analysis by digital imaging of fura-2 loaded transfected HEK-293 cells demonstrated that the short isoform exhibited K(+)-dependent Na+/Ca2+ exchange activity whereas the full-length isoform did not. The latter was retained within the endoplasmic reticulum, whereas the short isoform was present at the plasma membrane in transfected cells. Immunofluorescence studies examining NCKX6 expression in native tissue using an NCKX6-specific antibody showed intense labeling of the cardiac sarcolemmal membrane. The discovery of NCKX6 therefore reveals a novel member of the Na+/Ca2+ exchanger superfamily whose ubiquitous expression in all tissues suggests an important role for K(+)-dependent Na+/Ca2+ exchange in maintaining cellular Ca2+ homeostasis in diverse tissues and cell types.

Increased caveolin-1 expression in Alzheimer’s disease brain

Increasing evidence suggests that cholesterol plays a central role in the pathophysiology of Alzheimer’s disease (AD). Caveolin is a cholesterol-binding membrane protein involved in cellular cholesterol transport. We investigated the changes in the protein amount of hippocampal caveolin of autopsy-confirmed AD and aged-matched control subjects. Our results demonstrate that caveolin protein levels in the hippocampus and caveolin mRNA in the frontal cortex are up-regulated in AD by approximately two-fold, compared to control brains. These results suggest a relationship between caveolin-1 expression levels and a dysregulation of cholesterol homeostasis at the plasma membrane of brain cells. In support of this hypothesis, a significant increase in caveolin protein levels has also been observed in hippocampal tissue from ApoE-deficient (knockout) and aged wild-type mice; two situations associated with modifications of transbilayer distribution of cholesterol in brain synaptic plasma membranes. These results indicate that caveolin over-expression is linked to alterations of cholesterol distribution in the plasma membrane of brain cells and are consistent with the notion of a deterioration of cholesterol homeostasis in AD.

Degradation of endomorphin-2 at the supraspinal level in mice is initiated by dipeptidyl peptidase IV: an in vitro and in vivo study

Endomorphin-2 (Tyr–Pro–Phe–PheNH2) was discovered as an endogenous ligand for the μ-opioid receptor. The physiological function of endomorphin-2 as a neurotransmitter or neuromodulator may cease through the rapid enzymatic process in the synapse of brain, as for other neuropeptides. The present study was conducted to examine the metabolism of endomorphin-2 by synaptic membranes prepared from mouse brain. Major metabolites were free tyrosine, free phenylalanine, Tyr–Pro and PheNH2. Both the degradation of endomorphin-2 and the accumulation of major metabolites were inhibited by specific inhibitors of dipeptidyl peptidase IV, such as diprotin A and B. On the other hand, the accumulation of Phe–PheNH2 and Pro–Phe–PheNH2 was increased in the presence of bestatin, an aminopeptidase inhibitor, whereas that of free phenylalanine and PheNH2 was decreased. Furthermore, purified dipeptidyl peptidase IV hydrolyzed endomorphin-2 at the cleavage site, Pro2–Phe3 bond. Thus, degradation of endomorphin-2 by brain synaptic membranes seems to take place mainly through the cleavage of Pro2–Phe3 bond by dipeptidyl peptidase IV, followed by release of free phenylalanine and PheNH2 from the liberated fragment, Phe–PheNH2 by aminopeptidase. We have also examined that the effect of diprotin A on the antinociception induced by intracerebroventricularly administered endomorphin-2 in the mouse paw withdrawal test. Diprotin A simultaneously injected with endomorphin-2 enhanced endomorphin-2-induced antinociception. These results indicate that dipeptidyl peptidase IV may be an important peptidase responsible for terminating endomorphin-2-induced antinociception at the supraspinal level in mice.

A specific taurine recognition site in the rabbit brain is responsible for taurine effects on thermoregulation.

(1) Taurine and GABA are recognized as endogenous cryogens. In a previous study, some structural analogues of taurine, namely 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (TAG), 2-aminoethylarsonic (AEA), 2-hydroxyethanesulfonic (ISE) and (+/-)cis-2-aminocyclohexane sulfonic acids (CAHS) have been shown to displace [(3)H]taurine binding from rabbit brain synaptic membrane preparations, without interacting either with GABA-ergic systems, nor with taurine uptake mechanism, thus behaving like direct taurinergic agents. (2) To answer the question whether the role of taurine as an endogenous cryogen depends on the activation of GABA receptors or that of specific taurine receptor(s), taurine or the above structural analogues were injected intracerebroventricularly in conscious, restrained rabbits singularly or in combination and their effects on rectal (RT)- and ear-skin temperature and gross motor behavior (GMB) were monitored. (3) Taurine (1.2 x 10(-6)-4.8 x 10(-5) mol) induced a dose-related hypothermia, vasodilation at ear vascular bed and inhibition of GMB. CAHS, at the highest dose tested (4.8 x 10(-5) mol) induced a taurine-like effect either on RT or GMB. On the contrary ISE, injected at the same doses of taurine, induced a dose-related hyperthermia, vasoconstriction and excitation of GMB. AEA and TAG caused a dose-related hyperthermia, but at doses higher than 1.2 x 10(-7) mol caused death within 24 h after treatment. (4) CAHS (4.8 x 10(-5) mol) antagonized the hyperthermic effect induced by TAG (1.2 x 10(-6) mol), AEA (1.2 x 10(-8) mol) or ISE (4.8 x 10(-5) mol). (5) In conclusion, these findings may indicate the existence of a recognition site specific for taurine, responsible for its effects on thermoregulation.

Synthesis and Biological Evaluation of Pyridine‐Modified Analogues of 3‐(2‐Aminoethoxy)pyridine as Novel Nicotinic Receptor Ligands.

ChemInformVolume 34, Issue 9 Heterocyclic Compounds Synthesis and Biological Evaluation of Pyridine-Modified Analogues of 3-(2-Aminoethoxy)pyridine as Novel Nicotinic Receptor Ligands. Nan-Horng Lin, Nan-Horng Lin Neurol. Urol. Dis. Res., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorLiming Dong, Liming Dong Neurol. Urol. Dis. Res., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorWilliam H. Bunnelle, William H. Bunnelle Neurol. Urol. Dis. Res., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorDavid J. Anderson, David J. Anderson Neurol. Urol. Dis. Res., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorMichael D. Meyer, Michael D. Meyer Neurol. Urol. Dis. Res., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this author Nan-Horng Lin, Nan-Horng Lin Neurol. Urol. Dis. Res., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorLiming Dong, Liming Dong Neurol. Urol. Dis. Res., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorWilliam H. Bunnelle, William H. Bunnelle Neurol. Urol. Dis. Res., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorDavid J. Anderson, David J. Anderson Neurol. Urol. Dis. Res., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this authorMichael D. Meyer, Michael D. Meyer Neurol. Urol. Dis. Res., Abbott Lab., Abbott Park, IL 60064, USASearch for more papers by this author First published: 05 March 2003 https://doi.org/10.1002/chin.200309123Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume34, Issue9March 4, 2003 RelatedInformation