A total of 137 upward stopping muons of minimum energy 1.6 GeV are observed by Super-Kamiokande during 516 detector live days. The measured muon flux is
0.39±0.04
(stat.)±0.02
(syst.)×10
−13
cm
−2s
...−1sr
−1
compared to an expected flux of
0.73±0.16
(theo.)×10
−13
cm
−2s
−1sr
−1
. Using our previously-published measurement of the upward through-going muon flux, we calculate the stopping/through-going flux ratio
R
, which has less theoretical uncertainty. The measured value of
R=0.22±0.02
(stat.)±0.01
(syst.)
is significantly smaller than the value 0.37
+0.05
−0.04(theo.) expected using the best theoretical information (the probability that the measured
R
is a statistical fluctuation below the expected value is 0.39%). A simultaneous fitting to zenith angle distributions of upward stopping and through-going muons gives a result which is consistent with the hypothesis of neutrino oscillations with the parameters sin
22
θ>0.7 and 1.5×10
−3<
Δm
2<1.5×10
−2 eV
2 at 90% confidence level, providing a confirmation of the observation of neutrino oscillations by Super-Kamiokande using the contained atmospheric neutrino events.
In an effort to develop selective antagonists for kappa opioid receptors, bivalent ligands that contain opioid antagonist pharmacophores derived from naltrexone or other morphinans were synthesized ...and tested on the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. The minimum requirements for kappa selectivity are at least one free phenolic OH group and one N-cyclopropyl or N-ally substituent. Several compounds (3, 8, 10) with kappa selectivity as good as or better than norbinaltorphimine (nor-BNI, 2) were discovered. The structure-activity relationship revealed that the pyrrole ring functions strictly as a spacer and does not contribute to kappa selectivity. The pharmacologic data suggest that only one antagonist pharmacophore may be required for kappa selectivity and that the other morphinan portion of the molecule confers selectivity by interacting with a unique subsite proximal to the antagonist pharmacophore recognition locus.
A series consisting of spiroindanyl (5−7), benzospiroindanyl (8−10), and spiroperinaphthyl (11) derivatives of naltrexone and oxymorphone were synthesized in order to investigate the role of an ...orthogonal-oriented “address” for δ opioid receptors. All of the ligands exhibited a preference for δ receptors in vitro. The 7-benzospiroindanyl derivative 8 (BSINTX) was the most selective δ opioid receptor antagonist in vitro. In mice BSINTX antagonized the δ1- selective agonist, d-Pen2,d-Pen5enkephalin without significantly affecting the antinociceptive potency of δ2, μ, and κ agonists. The results of this study are consistent with an orthogonally-oriented address favoring δ1 activity.
The fumaramate methyl ester derivatives of naltrexone (beta-FNA) and oxymorphone (beta-FOA) were both found to be reversible agonists on the guinea pig ileal longitudinal muscle preparation. In ...addition, beta-FNA possessed on irreversible antagonistic effect against morphine whereas beta-FOA had no such capacity. Analysis by pA2 values revealed that beta-FOA resembled pure agonists like morphine and enkephalin while beta-FNA resembled the mixed agonist-antagonists like nalorphine and pentazocine. The antagonism by beta-FNA was very selective in that it antagonized pure agonists but had little or no effect on the effects of either mixed agonist-antagonists, ethylketocyclazocine or other non-opiate-type agonists like norepinephrine.
A series of naltrindole-related ligands (4-10) with an N-methyl,N-phenethyl,N-cinnamyl, or an unsubstituted basic nitrogen were synthesized and tested for opioid agonist and antagonist activity in ...smooth muscle preparations and in mice. The nor compounds (4 and 6) and the phenethyl derivatives (5 and 8) displayed full agonist activity (IC50 = 85-179 nM) in the mouse vas deferens preparation (MVD) while the other members of the series exhibited partial agonist or weak antagonist activity. In the guinea pig ileum preparation (GPI), all compounds except 8 were partial agonists. The ligands that were evaluated in mice were found to produce antinociception that was not selectively mediated via delta opioid receptors. However, two of these ligands (4 and 5) appeared to be delta-selective opioid receptor antagonists at subthreshold doses for antinociception. The finding that all of the compounds bind selectively to delta opioid receptors in guinea pig brain membranes together with the in vitro pharmacology and in vivo antagonist studies suggests that the lack of delta agonist selectivity in vivo may be due to a number of factors, including a basic difference between the delta receptor system in the MVD and in the mouse brain. Further, it is suggested that the constellation of message and address components in the morphindole nucleus may tend to stabilize delta receptors in the brain in antagonist state.
The identification of opioid delta receptor subtypes in mouse brain led to the investigation of the nature of the opioid delta receptors in the mouse isolated vas deferens in vitro. Noncumulative ...concentration-effect curves were constructed for DPDPE (delta 1 agonist) and D-Ala2, Glu4deltorphin (delta 2 agonist) in control tissues, or in tissues which had been incubated with either D-Ala2, Leu5, Cys6 enkephalin (DALCE) (noncompetitive delta 1 antagonist) or 5'-naltrindole isothiocyanate (5'-NTII) (noncompetitive delta 2 antagonist). Incubation of the tissues with DALCE, under either oxygenated or nonoxygenated conditions, did not alter the concentration-effect curves for either agonist. In contrast, incubation of the tissues with 5'-NTII resulted in a significant rightward displacement of the concentration-effect curves of both DPDPE and D-Ala2, Glu4 deltorphin. Additionally, naltriben, a selective and competitive delta 2 antagonist, showed no significant difference in its ability to antagonize a fixed, submaximal concentration of either DPDPE or D-Ala2, Glu4deltorphin. Furthermore, there was no significant difference in the affinity of naloxone (i.e., pA2) at the receptor(s) acted upon by either DPDPE or D-Ala2, Glu4deltorphin. Tolerance to DPDPE or D-Ala2, Glu4deltorphin was produced by incubation of the tissues with these agonists; construction of the D-Ala2, Glu4deltorphin concentration-effect curve in DPDPE-tolerant tissues demonstrated cross-tolerance between these agonists and, conversely, construction of DPDPE concentration-effect curves in D-Ala2, Glu4deltorphin-tolerant tissues revealed cross-tolerance between these agonists.
The present study evaluated the effect of a brief exposure of mice to cold-water swim-stress (CWSS) on the antinociceptive potency of i.c.v. given morphine. No significant antinociceptive response ...could be demonstrated in the warm-water tail-flick test, 10 min after a 30-sec exposure of mice to water at 5 degrees C. However, the i.c.v. morphine dose-response curve in mice exposed to CWSS was displaced significantly to the left when compared to that obtained in control (i.e., non-CWSS-exposed) mice. Although coadministration of the delta antagonist, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH 1 (ICI 174,864), with i.c.v. morphine did not produce antagonism of the antinociceptive action of this mu opiate, the leftward displacement of the i.c.v. morphine dose-response curve seen in CWSS-exposed mice was blocked in ICI 174,864-treated mice suggesting involvement of opioid delta receptors in the modulatory effect. Pretreatment of mice with the delta-1 antagonist, D-Ala2, Leu5, Cys6 enkephalin, did not antagonize the antinociception of morphine and further did not antagonize the leftward displacement produced by exposure to CWSS. Pretreatment of mice with the delta-2 antagonist, 5'-isothiocyanate, also did not antagonize the antinociceptive effects of morphine but blocked the leftward displacement in the morphine dose-response curve associated with CWSS, suggesting involvement of an opioid delta-2 receptor in this effect. Pretreatment of mice with the mu antagonist, beta-funaltrexamine, produced a significant antagonism of the morphine antinociceptive effect as seen by a rightward displacement of the morphine dose-effect curve.
The extracellular matrix can have a profound effect upon the phenotype of cancer cells. Previous work has shown that growth of bladder cancer cells on a matrix derived from normal basement membrane ...suppresses many malignant features that are displayed when the cells are grown on a matrix that has been modified by malignant tumors. This work was undertaken to investigate proteome-level changes as determined by a new commercially available proteome display involving 2-dimensional chromatography for bladder cancer cells grown on different extracellular matrix preparations that modulate the expression of the malignant phenotype.
Depending on the matrix, between 1300 and 2000 distinct peaks were detected by two-dimensional chromatographic fractionation of 2.1-4.4 mg of total cellular protein. The fractions eluting from the reversed-phase fractionation were suitable for mass spectrometric identification following only lyophilization and trypsin digestion and achieved approximately 10-fold higher sensitivity than was obtained with gel-based separations. Abundant proteins that were unique to cells grown on one of the matrices were identified by mass spectrometry. Following concentration, peaks of 0.03 AU provided unambiguous identification of protein components when 10% of the sample was analyzed, whereas peaks of 0.05 AU was approximately the lower limit of detection when the entire sample was separated on a gel and in-gel digestion was used. Although some fractions were homogeneous, others were not, and up to 3 proteins per fraction were identified. Strong evidence for post-translational modification of the unique proteins was noted. All 13 of the unique proteins from cells grown on Matrigel were related to MYC pathway.
The system provides a viable alternative to 2-dimensional gel electrophoresis for proteomic display of biological systems. The findings suggest the importance of MYC to the malignant phenotype of bladder cancer cells.
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