Imidazo[1,2-b]Pyridazines. XVI. Synthesis and Central Nervous System Activities of Some 6-(Chloro, Alkylthio, Phenylthio, Benzylthio or Pyridinylmethylthio)-3-(unsubstituted, benzamidomethyl or methoxy)-2-(styryl or benzoyl)imidazo[1,2-b]pyridazines

1994 ◽  
Vol 47 (11) ◽  
pp. 1989 ◽  
Author(s):  
GB Barlin ◽  
LP Davies ◽  
PW Harrison ◽  
NW Jacobsen ◽  
AC Willis
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rat Brain ◽  
Plasma Membranes ◽  
Benzodiazepine Receptors ◽  
X Ray

Some 6-( chloro, alkylthio, phenylthio, benzylthio or pyridinylmethylthio )-3-( unsubstituted , benzamidomethyl or methoxy )-2-styrylimidazo[1,2-b] pyridazines and 6-chloro-3-( unsubstituted and benzamidomethyl )-2-benzoylimidazo[1,2-b] pyridazines have been prepared and tested for their ability to displace [3H]diazepam from rat brain plasma membranes. The structures of 6-chloro-2-benzoyl[and 6-fluoro-2-(4′-tolyl)] imidazo [1,2-b] pyridazine have been confirmed by X-ray analyses. The reactions of 6-methylthio(and 6-phenylthio)pyridazin-3-amines with 3-bromo-1-phenylpropane-1,2-dione also have been investigated. The 6-substituted 3-unsubstituted 2-styryl(and benzoyl ) imidazo [1,2-b] pyridazines did not bind strongly to rat brain benzodiazepine receptors; nor did the 3-benzamidomethyl or 3-methoxy derivatives (cf. the 2-phenyl analogues). However, 3-benzamidomethyl-6-(pyridin-3-ylmethylthio)-2-styrylimidazo[1,2-b] pyridazine was an exception with IC50 68 nM.

Imidazo[1,2-b]Pyridazines. VI. Syntheses and Central Nervous System Activities of Some 6-(Alkoxy- and Methylthio-phenoxy and Methoxybenzylthio)-3-methoxy-2-phenyl(substituted phenyl and pyridinyl)Imidazo[1,2-b]pyridazines

1989 ◽  
Vol 42 (10) ◽  
pp. 1735 ◽  
Author(s):  
GB Barlin ◽  
LP Davies ◽  
SJ Ireland ◽  
MML Ngu
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rat Brain ◽  
Plasma Membranes ◽  
Active Member ◽  
Type Analysis ◽  
Related Series

Series of 6-( alkoxy - and methylthio-phenoxy )-2-phenyl(substituted phenyl and pyridiny1)imidazo[l,2-b]pyridazines and 3-methoxy-6-( methoxybenzylthio )-2-phenyl(substituted phenyl and pyridinyl ) imidazo[l,2-b]pyridazines have been prepared and subsequently tested for their ability to inhibit GABA-stimulated 3H-diazepam binding to rat brain plasma membranes. The 6( alkoxy- and methylthio-phenoxy ) and 6-( methoxybenzylthio) compounds were much more effective in the displacement studies than the parent 6-phenoxy or 6-benzylthio compounds respectively. 3-Methoxy-6-(2′-methoxyphenoxy)-2-phenylimidazo[l,2-b]pyridazine (GBLD-167, IC50 70 nm) was 16 times more effective than its 3-methoxy-6-phenoxy analogue (GBLD-163, IC50 1120 nM ) and the 3-methoxy-6-(21-methoxybenzylthio)-2-phenyl compound (GELD-214, 1C50 9 nM ) was two and a half times more active than its 6-benzylthio-3-methoxy analogue (GBLD-137, IC50 22 nM ). The most active member of the 6-phenoxy series was the 2-(41-fluorophenyl)-3-methoxy-6- (2″-methoxyphenoxy) compound (GBLD-255, IC50 30 nM ) and, within the 6-benzylthio series, the 2-(4′-fluorophenyl, 3′-aminophenyl, and pyridin-31-yl)-3-methoxy-6-(3″-methoxybenzylthio) compounds (GBLD-233, 301 and 296) all gave IC50 5 nM. A Hansch -type analysis of the results for these two closely related series of compounds indicates that electron-donating substituents in 2-(para substituted phenyl) derivatives favour binding, but bulky substituents hinder this effect.

Imidazo[1,2-B]Pyridazines. III. Syntheses and Central Nervous-System Activities of Some 6-Chloro-3-methoxy (and ethoxy)-2-aryl (and heteroaryl)imidazo[1,2-B]pyridazines

1988 ◽  
Vol 41 (8) ◽  
pp. 1149 ◽  
Author(s):  
GB Barlin ◽  
LP Davies ◽  
MML Ngu
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rat Brain ◽  
Active Compound ◽  
Plasma Membranes ◽  
Aminobutyric Acid ◽  
Ic50 Value ◽  
Standard Assay ◽  
Assay Conditions

The synthesis of a series of 6-chloro-3-methoxy(and ethoxy )-2- phenyl[and (variously substituted phenyl), thienyl, and naphthalenyl ] imidazo [1,2-b] pyridazines and a 6-fluoro analogue are reported. These compounds were tested for their ability to displace [3H]diazepam bound to washed rat brain plasma membranes. Under standard assay conditions (see Experimental) and in the presence of 100 μM γ- aminobutyric acid, 6-chloro-3-methoxy-2-(p-tolyl ) imidazo [1,2- b] pyridazine was the most active compound with an IC50 value of 148 nM (cf. diazepam, with IC50 of 4.2 nM).

Imidazo[1,2-b]pyridazines. IV. Syntheses and Central Nervous System Activities of Some 3-Methoxy-6-phenoxy(Substituted Phenoxy and Naphthyloxy)-2-phenylimidazo[1,2-b]pyridazines

1988 ◽  
Vol 41 (11) ◽  
pp. 1735 ◽  
Author(s):  
GB Barlin ◽  
LP Davies ◽  
MML Ngu
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rat Brain ◽  
Peripheral Nervous System ◽  
Pharmacological Activity ◽  
Plasma Membranes ◽  
Active Compounds ◽  
Ic50 Values ◽  
Potential Activity ◽  
Made In

Syntheses are reported for some 3-methoxy-6-phenoxy(substituted phenoxy and naphthyloxy )-2-phenylimidazo[1,2-b] pyridazines; they were made in order to study their possible pharmacological activity in the mammalian central and peripheral nervous system. In initial biological screens to detect compounds with potential activity at receptors for the benzodiazepine class of drugs, the most active compounds were 3-methoxy-6-(2′-methylthiophenoxy)- and 6-(2′-dimethylaminophenoxy )-3-methoxy-2-phenylimidazo[1,2-b] pyridazine. Their respective IC50 values for displacement of 3H-diazepam (IC50 for unlabelled diazepam, 4.2 nM ) from rat brain plasma membranes (measured in the presence of 100 μM GABA) were 112 and 149 nM.

Imidazo[1,2-b]pyridazines. VII. Syntheses and Central Nervous System Activities of Some 3-Alkoxy-6-benzyloxy (and methoxy-benzyloxy)-2-phenyl(substituted phenyl or pyridinyl)imidazo[1,2-b]pyridazines

1989 ◽  
Vol 42 (10) ◽  
pp. 1749 ◽  
Author(s):  
GB Barlin ◽  
LP Davies ◽  
MML Ngu
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rat Brain ◽  
Active Compound ◽  
Plasma Membranes ◽  
Ring System ◽  
Derivatives Of

A series of 15 3-alkoxy-6-benzyloxy( methoxybenzyloxy )-2-phenyl( sbstitted phenyl and pyridinyl )imidazo[l,2-b]pyridazines has been prepared and each compound tested for its ability to displace 3H-diazepam from rat brain plasma membranes. The results have been compared with data previously obtained for other derivatives of this ring system. Compounds containing 6(o- or m- methoxybenzyloxy ) groups were more effective in the displacement of 3H-diazepam than those with the 6-benzyloxy group; and the most active compound was 2-(p- fluorophenyl )-3-methoxy-6-(m- methoxybenzyloxy )imidazo[l,2 b]pyridazine with IC50 1.5 nM.

scholarly journals Acid-beta-glycerophosphatase reaction products in the central nervous system mitochondria following x-ray irradiation.

1975 ◽  
Vol 23 (6) ◽  
pp. 402-410 ◽  
Author(s):  
L Roizin ◽  
D Orlovskaja ◽  
J C Liu ◽  
A L Carsten
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acid Phosphatase ◽  
Enzyme Reaction ◽  
Reaction Products ◽  
Huntington's Chorea ◽  
X Ray ◽  
System A ◽  
Chemical Lesion ◽  
The Central Nervous System

A survey of the literature to date on the enzyme histochemistry of intracellular organelles has not yielded any reference to the presence of acid phosphatase reaction products in the mammalian mitochondria of the central nervous system. A combination of Gomori's acid phosphatase mehtod, however, with standard electron microscopy has disclosed the presence of enzyme reaction products in the mitochondria of the central nervous system of rats from 2 hr to 22 weeks after x-ray irradiation, as well as in a cerebral biopsy performed on a patient affected by Huntington's chorea. No enzyme reaction products, on the other hand, were observed in serial sections that had been incubated in substrates either containing sodium fluoride or lacking in beta-glycerophosphate. The abnormal mitochondrial enzyme reaction (chemical lesion) is considered to be the consequenco of the pathologic process affecting the ultrastructural-chemical organization of the organelle.

scholarly journals Membrane-type 1 Matrix Metalloprotease (MT1-MMP) Enables Invasive Migration of Glioma Cells in Central Nervous System White Matter

1999 ◽  
Vol 144 (2) ◽  
pp. 373-384 ◽  
Author(s):  
Ann T.J. Beliën ◽  
Paolo A. Paganetti ◽  
Martin E. Schwab
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
White Matter ◽  
Plasma Membranes ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
C6 Glioma ◽  
C6 Glioma Cells ◽  
Glioblastoma Cells

Invasive glioma cells migrate preferentially along central nervous system (CNS) white matter fiber tracts irrespective of the fact that CNS myelin contains proteins that inhibit cell migration and neurite outgrowth. Previous work has demonstrated that to migrate on a myelin substrate and to overcome its inhibitory effect, rat C6 and human glioblastoma cells require a membrane-bound metalloproteolytic activity (C6-MP) which shares several biochemical and pharmacological characteristics with MT1-MMP. We show now that MT1-MMP is expressed on the surface of rat C6 glioblastoma cells and is coenriched with C6-MP activity. Immunodepletion of C6-MP activity is achieved with an anti–MT1-MMP antibody. These data suggest that MT1-MMP and the C6-MP are closely related or identical. When mouse 3T3 fibroblasts were transfected with MT1-MMP they acquired the ability to spread and migrate on the nonpermissive myelin substrate and to infiltrate into adult rat optic nerve explants. MT1-MMP–transfected fibroblasts and C6 glioma cells were able to digest bNI-220, one of the most potent CNS myelin inhibitory proteins. Plasma membranes of both MT1-MMP–transfected fibroblasts and C6 glioma cells inactivated inhibitory myelin extracts, and this activity was sensitive to the same protease inhibitors. Interestingly, pretreatment of CNS myelin with gelatinase A/MMP-2 could not inactivate its inhibitory property. These data imply an important role of MT1-MMP in spreading and migration of glioma cells on white matter constituents in vitro and point to a function of MT1-MMP in the invasive behavior of malignant gliomas in the CNS in vivo.

Sign in / Sign up

Export Citation Format

Share Document