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PubMed2005

Interactions among mu- and delta-opioid receptors, especially putative delta1- and delta2-opioid receptors, promote dopamine release in the nucleus accumbens.

The effect of interactions among mu- and delta-opioid receptors, especially the putative delta(1)- and delta(2)-opioid receptors, in the nucleus accumbens on accumbal dopamine release was investigated in awake rats by in vivo brain microdialysis. In agreement with previous studies, perfusion of the nucleus accumbens with the mu-, delta(1)- and delta(2)-opioid receptor agonists [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), [D-Pen(2,5)]-enkephalin (DPDPE) and [D-Ser(2)]Leu-enkephalin-Thr(6), respectively, significantly enhanced the extracellular amount of accumbal dopamine in a dose-related manner (5.0 nmol and 50.0 nmol). However, the highest concentration tested (50.0 nmol) of DAMGO induced a biphasic effect, i.e. a rapid onset increase lasting for 75 min followed by a slower onset gradual and prolonged increase. The mu-opioid receptor antagonist D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) (0.15 nmol) primarily reduced the DAMGO-induced second component. The delta(1)-opioid receptor antagonist (E)-7-benzylidenenaltrexone (0.15 nmol) significantly reduced the first component and abolished the second component induced by DAMGO, while the delta(2)-opioid receptor antagonist naltriben (1.5 nmol) significantly reduced only the first component. The DPDPE (50.0 nmol)-induced dopamine increase was almost completely abolished by (E)-7-benzylidenenaltrexone, but only partially reduced by D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) and naltriben. The [D-Ser(2)]Leu-enkephalin-Thr(6) (50.0 nmol)-induced dopamine increase was almost completely abolished by naltriben, but not at all by D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) and (E)-7-benzylidenenaltrexone. The non-selective opioid receptor antagonist naloxone (0.75 and 1.5 nmol) dose-dependently reduced the effects of DAMGO, DPDPE and [D-Ser(2)]Leu-enkephalin-Thr(6) but only to about 10-25% of the control values. Moreover, perfusion with the sodium channel blocker tetrodotoxin (0.1 nmol) reduced the DAMGO-induced dopamine increase by 75%, while it almost completely abolished the increase induced by DPDPE or [D-Ser(2)]Leu-enkephalin-Thr(6). The results show that stimulation of mu-opioid receptors or, to a lesser degree, delta(1)-opioid receptors results in a large naloxone-sensitive increase and a small naloxone-insensitive increase of extracellular dopamine. It is suggested that the naloxone-insensitive component is also tetrodotoxin-insensitive. Furthermore, it is hypothesized that stimulation of mu-opioid receptors activates delta(1)-receptors, which in turn activate delta(2)-opioid receptors, thereby giving rise to a rapid onset increase of extracellular dopamine. In addition, it is hypothesized that stimulation of another group of mu-opioid receptors activates a second group of delta(1)-opioid receptors that is not coupled to delta(2)-opioid receptors and mediates a slow onset increase of extracellular dopamine. Finally, it is suggested that stimulation of delta(1)- or delta(2)-opioid receptors inhibits mu-opioid receptors involved in the slow onset increase in extracellular dopamine, whereas stimulation of delta(1)-, but not delta(2)-, opioid receptors is suggested to activate mu-opioid receptors involved in the rapid increase in extracellular dopamine.

Analgesics, Opioid↗
PubMed2007

alpha7 Nicotinic receptor gene delivery into mouse hippocampal neurons leads to functional receptor expression, improved spatial memory-related performance, and tau hyperphosphorylation.

Brain alpha7 nicotinic receptors have become therapeutic targets for Alzheimer's disease (AD) based on their memory-enhancing and neuroprotective actions. This study investigated the feasibility of increasing neuronal alpha7 receptor functions using a gene delivery approach based on neuron-selective recombinant adeno-associated virus (rAAV)-derived vectors. In order to determine whether alpha7 receptor-mediated cytotoxicity was dependent on receptor density, rat alpha7 nicotinic receptors were expressed at high concentrations in GH4C1 cells as measured with nicotine-displaceable [3H]methyllycaconitine (MLA) binding. The potency of GTS-21 (an alpha7 receptor agonist) to induce cell loss was similar in these cells to that seen in pheochromocytoma (PC12) cells expressing nine-times-lower receptor levels, suggesting that cytotoxicity was more dependent on agonist concentration than receptor density. Hippocampal transduction with rat alpha7 nicotinic receptors increased [3H]MLA binding in this region in wild type and alpha7 receptor-knockout (KO) mice without apparent cytotoxicity. No difference was observed in Kd values for MLA binding between endogenous and transgenic receptors. Single cell recordings demonstrated that dentate granule cells that normally have no alpha7 receptor response did so following alpha7 receptor gene delivery in wild type mice. Recovery of alpha7 function was also observed in stratum oriens and stratum radiatum neurons of KO mice following gene delivery. Wild type mice exhibited improved acquisition performance in the Morris water task 1 month after bilateral hippocampal transductions with the rat alpha7 receptor gene compared with green fluorescent protein-transduced controls. However, both groups reached similar training levels and there was no difference in subsequent probe performance. Finally, this gene delivery approach was used to test whether alpha7 receptors affect tau-phosphorylation. Chronic (i.e. 2 month but not 2 week) expression of high levels of alpha7 receptors in hippocampus increased AT8 staining characteristic of hyperphosphorylated tau in that region, indicating that endogenous agonist-mediated receptor activation may be able to modulate this process.

Aconitine↗
PubMed2004

Chlorobenzylidine-calf thymus DNA interaction II: circular dichroism and nuclear magnetic resonance studies.

The binding of chlorobenzylidine to calf thymus DNA has been studied in detail by means of circular dichroism (CD), nuclear magnetic resonance (1H NMR), viscosimetry and denaturation temperature (Tm). Chlorobenzylidine is found to intercalate between base pairs of DNA as evidence by: (1) induced circular dichroism; (2) broadened 1H NMR signals; (3) enhanced viscosity; and (4) increased denaturation temperature of the DNA helix. In addition, Scatchard plot from CD titration data gives a binding constant of 2.6 x 10(4) M(-1) and a binding site size of 4 base pairs at 25 degrees C. Matrix rank analysis shows that there are three main components contributing to the observed CD spectra. The nuclear magnetic resonance experiment shows that the planar aromatic ring of tetrahydroberberine group in chlorobenzylidine intercalates between the base pairs of DNA when chlorobenzylidine is bound to DNA.

Animals↗
PubMed2006

Vibrational assignment of the normal modes of 2-phenyl-4-(4-methoxy benzylidene)-2-oxazolin-5-one via FTIR and Raman spectra, and ab inito calculations.

Raman and FTIR spectra of 2-phenyl-4-(4-methoxy benzylidene)-2-oxazolin-5-one were recorded in the regions, 100-3300 and 400-4000 cm(-1), respectively. Vibrational frequencies and intensities of the fundamental modes of this hetrocyclic organic molecule were computed using ab initio as well as AM1 semiempirical molecular orbital methods. Ab initio calculations were carried out with basis set up to RHF/6-311G. Conformational studies regarding the effect of moving the methoxy group in the 2-phenyl-4-(4-methoxy benzylidene)-2-oxazolin-5-one molecule to a different position on the ring was also carried out. Observed vibrational wavenumbers were found to be mostly consistent with ab initio values. The most intense mode of vibration observed at 1250 cm(-1) in Raman spectra, also observed as a strong band in FTIR, was assigned as C-O stretching vibration in the methoxy group. Asymmetric stretching vibrations between CC and CN bonds was predicted as most intense mode by our ab initio calculation.

Benzylidene Compounds↗
PubMed2001

Intragastric DMXB-A, an alpha7 nicotinic agonist, improves deficient sensory inhibition in DBA/2 mice.

BACKGROUND: Abnormal sensory inhibition is observed in the majority of schizophrenic patients. DBA/2 mice spontaneously exhibit a similar deficit in sensory inhibition and thus provide a model for drug development targeted to this physiologic abnormality. The impaired sensory inhibition is characterized by diminished response of the hippocampal evoked potential to the second of closely paired auditory stimuli (500-m/sec interstimulus interval). Subnormal levels of hippocampal alpha7 nicotinic cholinergic receptors are associated with the deficient sensory inhibition in both DBA/2 mice and people with schizophrenia. METHODS: Our study examined the inhibition of the P20-N40 auditory evoked potential in DBA/2 mice after intragastric administration of DMXB-A (3-2,4-dimethoxybenzylidine anabaseine), an alpha7 nicotinic receptor partial agonist. After presentation of auditory stimuli, electroencephalographic responses were recorded and measured to monitor the effects of the DMXB-A, alone and in combination with selective nicotinic antagonists. RESULTS: Gastric administration of DMXB-A (10 mg/kg) improved sensory inhibition in DBA/2 mice. This improvement was blocked by alpha-bungarotoxin, but not mecamylamine, indicating that DMXB-A exerts its effects through the alpha7 nicotinic receptor. CONCLUSIONS: Intragastrically administered DMXB-A improves deficient sensory inhibition in DBA/2 mice through stimulation of alpha7 nicotinic receptors. These studies agree with results from previous studies with subcutaneously administered DMXB-A.

Acoustic Stimulation↗
PubMed2000

Inhibition of nitric oxide synthase prevents alpha 7 nicotinic receptor-mediated restoration of inhibitory auditory gating in rat hippocampus.

The hippocampus rapidly inhibits its response to repetitive auditory stimulation, an example of an auditory sensory gating mechanism involved in human psychopathology. The neuronal basis of this inhibitory gating mechanism has been investigated in rats. Activation of the alpha 7 nicotinic receptor is required. alpha 7 nicotinic receptor activation also releases nitric oxide in the hippocampus and blockade of nitric oxide synthase reduces inhibitory gating of auditory response. There has not been a direct demonstration that blockade of nitric oxide synthase specifically prevents alpha 7 nicotinic receptor activation of the inhibition of auditory response. Therefore, the goal of the present study was to determine whether this functional effect of alpha 7 receptor activation requires release of nitric oxide. Lesions of the fimbria-fornix disrupt auditory gating by preventing cholinergic stimulation of the hippocampus. Following recovery from this surgery, rats were administered 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A; 10 mg/kg, sc), an agonist at the alpha 7 receptor. DMXB-A restored auditory gating in the fimbria-fornix-lesioned rats, indicating that activation of the alpha 7 nicotinic receptor alone is sufficient to restore auditory gating following lesions of the fimbria-fornix. However, intracerebroventricular infusion of N(omega)-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, blocked the DMXB-A-mediated restoration of auditory gating; infusion of the inactive D-enantiomer did not. Restoration of auditory gating by DMXB-A in the fimbria-fornix-lesioned rats was blocked by intracerebroventricular infusion of alpha-bungarotoxin, but not by mecamylamine or dihydro-beta-erythroidine. Together, these data support the hypothesis that nitric oxide mediates alpha 7 nicotinic receptor activation of gating of auditory response in rat hippocampus.

Acoustic Stimulation↗
PubMed1996

Role of opioid receptors (mu, delta 1, delta 2) in modulating responses of nociceptive neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in the rat.

This report describes the effects of intravenously administered agonists and antagonists at mu-, delta 1- and delta 2-opioid receptors on the A delta- and C-fiber-evoked responses of trigeminal nociceptive neurons in anesthetized rats. Extracellular single unit recordings were made from 61 nociceptive neurons (23 NS, 38 WDR) in the superficial and 37 nociceptive neurons (3 NS, 34 WDR) in the deeper dorsal horn of the medulla (trigeminal nucleus caudalis). Administration of either the delta 1-receptor agonist [D-Pen2,5]enkephalin (DPDPE; 0.05-2 mg/kg), the delta 2-receptor agonist [D-Ala2, Glu4]deltorphin (DELT; 1-2 mg/kg) or the mu-receptor agonist [D-Ala2, N-MePhe4, Gly5-ol]enkephalin (DAMGO; 0.05-1 mg/kg) inhibited the A delta- and C-fiber-evoked responses of nociceptive neurons in the superficial and deeper dorsal horn. The inhibitory effect was more pronounced on the C-fiber-evoked responses than on the A delta-fiber-evoked responses. In other neurons, DPDPE also produced facilitation, or inhibition followed by facilitation, or differential effects (inhibition of the C-fiber-evoked responses and facilitation of the A delta-fiber-evoked responses) on the A delta- and C-fiber-evoked responses. The effects of DPDPE were antagonized by 7-benzylidenenaltrexone (BNTX, 0.4-1 mg/kg), a delta 1-receptor antagonist, in 88% (7/8) of neurons. Naltriben (NTB, 0.7-1 mg/kg), a delta 2-receptor antagonist, antagonized the effect of both DELT and DPDPE. A smaller dose of NTB (0.3 mg/kg), which failed to reverse the effects of DPDPE in 100% (4/4) of neurons, effectively antagonized the effects of DELT in 100% (6/6) of neurons. The inhibitory action of DAMGO was completely antagonized by naloxone (0.2 mg/kg) in 100% (6/6) of neurons. The results of the present investigation suggest that: (1) mu-, delta 1- and delta 2-opioid receptors play an important role in the inhibitory modulation of the A delta- and C-fiber-evoked responses of nociceptive neurons in the superficial and deeper dorsal horn of the medulla; (2) selective inhibition of the C-fiber-evoked responses by activation of opioid receptors may account for the opioid-mediated selective suppression of second or persistent pain as compared to first pain; and (3) NTB, in a limited dose range, can discriminate between delta 1- and delta 2-opioid receptor subtypes.

Animals↗
PubMed1998

Nicotinic alpha 7 receptors protect against glutamate neurotoxicity and neuronal ischemic damage.

The alpha7 receptor agonist dimethoxybenzylidene anabaseine (DMXB) protected rat neocortical neurons against excitotoxicity administered 24 h before, but not concomitantly with, NMDA. This action was blocked by nicotinic but not muscarinic antagonists. DMXB (1 mg/kg i.p.) also reduced infarct size in rats when injected 24 h before, but not during, focal ischemic insults. In a mecamylamine-sensitive manner, alpha7 receptors appear neuroprotective in non-apoptotic model.

Animals↗
PubMed1998

Neuroprotective effects of 2,4-dimethoxybenzylidene anabaseine (DMXB) and tetrahydroaminoacridine (THA) in neocortices of nucleus basalis lesioned rats.

The nicotinic alpha7 agonist dimethoxybenzilidene anabaseine (DMXB) and cholinesterase inhibitor tetrahydroaminoacridine (THA) were investigated in a trans-synaptic model for neocortical atrophy and degeneration following nucleus basalis lesions. Bilateral lesions reduced parietal neuronal density in layers II-V 8 months later. DMXB administered i.p. daily to rats for 3 months attenuated this loss in layers II-V at a 1 mg/kg i.p. dose. A lower, 0.2 mg/kg i.p. dose, was neuroprotective in layer IV only. THA (1 mg/kg i.p.) also protected against neocortical Nissl-staining deficits.

Animals↗
PubMed1997

3-[2,4-Dimethoxybenzylidene]anabaseine (DMXB) selectively activates rat alpha7 receptors and improves memory-related behaviors in a mecamylamine-sensitive manner.

The alpha7 nicotinic receptor agonist 3-[2,4-dimethoxybenzylidene]anabaseine (DMXB; GTS-21) was investigated for its ability to: (1) activate a variety of nicotinic receptor subtypes in Xenopus oocytes; (2) improve passive avoidance and spatial Morris water task performances in mecamylamine-sensitive manners in bilaterally nucleus basalis lesioned rats; and (3) elevate high-affinity [3H]acetylcholine (ACh) and high-affinity alpha-[125I]bungarotoxin binding in rat neocortex following 2 weeks of daily injections. DMXB (100 microM) activated alpha7 homo-oligomeric receptors, without significant activity at alpha2-, alpha3- and alpha4-containing subtypes. Mecamylamine blocked rat alpha7 receptors weakly if co-administered with agonist, but much more potently when pre-applied. Bilateral ibotenic acid lesions of the nucleus basalis interfered with passive avoidance and spatial memory-related behaviors. DMXB (0.5 mg/kg, i.p.) improved passive avoidance behavior in lesioned animals in a mecamylamine-sensitive manner. DMXB (0.5 mg/kg 15 min before each session) also improved performance in the training and probe components of the Morris water task. DMXB-induced improvement in the probe component but not the training phase was mecamylamine-sensitive. [3H]ACh binding was elevated after 14 days of daily i.p. injections with 0.2 mg/kg nicotine but not after 1 mg/kg DMXB. Neither drug elevated high-affinity alpha-[125I]bungarorotoxin binding over this interval.

Animals↗
PubMed1997

Role of spinal delta1 and delta2 opioid receptors in the antinociception produced by microinjection of L-glutamate in the ventromedial medulla of the rat.

This study examined the contribution of spinal delta1 and delta2 opioid receptors to the antinociception produced by microinjection of L-glutamate in either the nucleus raphe magnus (NRM) or the nucleus reticularis gigantocellularis pars alpha (NGCp alpha) of the rat. Intrathecal (i.t.) pretreatment with 1 microg of 7-benzylidinenaltrexone (BNTX), a delta1 opioid receptor antagonist, did not antagonize the increase in tail flick latency (TFL) produced by microinjection of L-glutamate in either the NRM or the NGCp alpha. In contrast, i.t. pretreatment with 3 microg of naltriben (NTB), a delta2 opioid receptor antagonist, completely antagonized the increase in TFL evoked by microinjection of L-glutamate in the NRM, but did not antagonize the increase in TFL evoked from the NGCp alpha. These results suggest that the antinociception produced by activation of these bulbospinal pathways is predominantly mediated by spinal delta2 opioid receptors and that there is little, if any, contribution by spinal delta1 opioid receptors.

Analgesics↗
PubMed1998

Gestational and ovarian sex steroid antinociception: synergy between spinal kappa and delta opioid systems.

Pain thresholds are elevated during gestation and following the simulation of pregnancy blood levels of estrogen and progesterone (hormone simulated pregnancy; HSP). The analgesia associated with both conditions is opioid-mediated and results from the activation of spinal cord kappa and delta (but not mu) opiate receptors. Blockade of spinal kappa or delta opiate receptors, individually, can abolish the antinociception associated with either gestational day 20 or day 19 of HSP. Surprisingly, during either physiological pregnancy or HSP, the magnitude of reduction in the increment in jump thresholds following the combined intrathecal application of suboptimum concentrations of kappa and delta antagonists is indistinguishable from that observed following their individual intrathecal application. These data indicate that gestational and ovarian sex steroid-induced antinociception is not simply the sum of the independent analgesic effects of spinal kappa and delta opioid systems but requires their coincident activation. It is suggested that the synergy that has been reported following the exogenous intrathecal application of kappa and delta opioids also occurs between their endogenous counterparts and underlies the intrinsic analgesia associated with each condition. Utilization of such a mechanism allows for significant physiological effects (analgesia) to be achieved with doses of relevant substrates (dynorphin and enkephalin) which alone would produce minimal receptor activation (and analgesia). This would minimize tolerance and dependence formation.

Animals↗
PubMed1999

Characterization of the neuroprotective and toxic effects of alpha7 nicotinic receptor activation in PC12 cells.

The alpha7 nicotinic receptor partial agonist DMXB protected differentiated PC12 cells from NGF+ serum deprivation over a concentration range (1-10 microM) that correlated with activation of protein kinase C. Increased toxicity was observed at a higher concentration of DMXB (30 microM) that did not elevate protein kinase C activity, but did increase tyrosine protein kinase activity. Neuroprotection was blocked with the protein kinase C-inhibitor bis-indolemaleimide, while toxicity was attenuated with the tyrosine protein kinase-antagonists herbimycin and genistein. The alpha7-selective antagonist methyllyconitine attenuated both the protective and toxic actions of DMXB, but in temporally distinct manners. Methyllyconitine (1 microM) attenuated toxicity when added 10 s before, but not 10 s after, 30 microM DMXB. In contrast, it blocked neuroprotection when added 10 min post-agonist addition. This temporal difference in receptor-activation that was necessary for protection vs. toxicity reflected the time courses for agonist-induced desensitization of the receptor expressed in Xenopus oocytes. These results indicate that alpha7 nicotinic receptors act through different intracellular transduction processes to protect or kill cells. Further, they suggest that the transduction processes may be differentially activated depending on the amplitude and duration of calcium signals.

Animals↗
PubMed1975

Some benzylidene acetal derivatives of theophylline nucleosides.

The reaction of some hexopyranosyltheophylline nucleosides with benzaldehyde in the presence of zinc chloride gave the expected benzylidene acetals. Thus, 7-alpha-D-mannopyranosyltheophylline gave the 2',3':4',6'-diacetal as a mixture of diastereoisomers, one of which was isolated. The beta-D-galacto- and beta-D-gluco-pyranosyltheophyllines gave the 4',6'-acetals, which were characterised as 2',3'-diesters. Mild, acidic hydrolysis of 7-(4,6-O-benzylidene-2,3-di-O-mesyl-beta-D-glucopyranosyl)theophylline gave 7-(2,3-di-O-mesyl-beta-D-glucopyranosyl)theophylline, and strongly basic hydrolysis gave 7-(2,3-anhydro-4,6-O-benzylidene-beta-D-allopyranosyl)theophylline. Ring-opening of this 2',3'-epoxide with iodide anion afforded mainly 7-(4,6-O-benzylidene-2-deozy-2-iodo-beta-D-altropyranosyl)theophylline, which was characterised as the 6'-acetate.

Benzylidene Compounds↗
PubMed1992

Rearrangement of unsaturated 2,4-O-benzylidenehexitol derivatives into C-glycosylbenzene derivatives.

Acetolysis of (Z)-1,3-di-O-acetyl-2,4-O-benzylidene-6-C-(2,4-dichlorophenyl)-D-xylo-he x- 5-enitol (3) afforded (E)-1,2,3,4-tetra-O-acetyl-6-C-(2,4-dichlorophenyl)-D-xylo-hex-5-enit ol and 2-C-[(R)-acetoxy(2,4-dichlorophenyl)methyl]-3,4,6-tri-O-acetyl-2-deoxy- beta-L-galacto- and -beta-L-gulo-hexopyranosylbenzene. The mechanism of this new rearrangement was studied by exchanging the substituents at C-1 and C-3 in 3 and those of the aromatic ring attached to C-6.

Benzene Derivatives↗
PubMed2002

Synthesis of natural beta-D-(1-->3)-glucopyranosyl oligosaccharides.

beta-D-(1-->3)-Glucan core structure derivatives corresponding to schizophyllan, epiglucan and lentinan were synthesized efficiently. 4,6-O-Benzylidenated glucopyranosyl acceptors were found to be helpful in the attempted beta-D-(1-->3) bond formation. The epiglucan pentasaccharide showed a weak anti-tumor activity in preliminary mice tests.

Animals↗
PubMed2003

Remote site bromination via a cascade rearrangement involving two bridging dioxonium species during oxidative cleavage of a benzylidene acetal.

Attempted cleavage of the benzylidene group of 3,5-O-benzylidene-2,6,7-tri-O-trimethylacetyl-D-glycero-D-gulo-heptono-1,4-lactone with N-bromosuccinimide led to the formation of a 7-bromo derivative with a benzoyl group in the 3-position and trimethylacetyl groups in the 5 and 6 positions. Analysis of the coupling constants in the proton NMR spectra indicated that both trimethylacetyl groups had participated to shift the crowded electron-deficient center formed at the 5-position by the decomposition of the bromobenzylidene group to the much more accessible 7-position. The net result of this cascade rearrangement was retention at both the C-5 and C-6 positions. This is an interesting example of a cascade rearrangement under strict entropic and stereo control the synthetic utility of which is being investigated.

Benzylidene Compounds↗