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. IX. Syntheses and Central Nervous System Activities of Some 3-Alkoxy-6-(o-alkoxy, o-methylthio- or o-fluoro-phenoxy)-2-arylimidazo[1,2-b]pyridazines

1990 ◽  
Vol 43 (3) ◽  
pp. 503 ◽  
Author(s):  
GB Barlin ◽  
LP Davies ◽  
SJ Ireland ◽  
CLY Khoo ◽  
TMT Nguyen
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rat Brain ◽  
Brain Membrane ◽  
Active Compounds ◽  
Ic50 Values

Syntheses are reported for a series of 6-(o-methoxy -, o-ethoxy -, o-methylthio - and o-fluoro-phenoxy )-3-( methoxy and ethoxy )-2- phenyl(substituted phenyl and pyridin-3″-yl) imidazo [1,2-b] pyridazines . IC50 values are reported for the displacement of 3H-diazepam from rat brain membrane by each of these compounds. The most active compounds were found to be 3-ethoxy-2-(p- fluorophenyl )-6-(o- methoxyphenoxy )-, 3-methoxy-6-(o- methoxyphenoxy )-2-(m-nitrophenyl )- and 3-methoxy-6-(o- methoxyphenoxy )-2-(3″,4″-methylenedioxy ) imidazo [1,2-b] pyridazines with IC5O values of 15, 18 and 19 nM respectively.

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. XII. Syntheses and Central Nervous System Activities of Some Substituted Imidazo[1,2-b]pyridazines and Related Imidazo[1,2-a]pyridines, Imidazo[1,2-a]pyrimidines and Imidazo[1,2-a]pyrazines

1992 ◽  
Vol 45 (5) ◽  
pp. 877 ◽  
Author(s):  
GB Barlin ◽  
LP Davies ◽  
SJ Ireland ◽  
MML Ngu ◽  
JK Zhang
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rat Brain ◽  
Alkyl Group ◽  
Significant Loss ◽  
Aryl Group ◽  
Brain Membrane ◽  
Ic50 Values

Syntheses are reported for some 6-chloro(alkoxy,alkylthio and pheny1thio)-3-benzamidomethyl-(acetamidomethyl and methoxy)-2-arylimidazo[1,2-apyridines and some corresponding imidazo- [1,2- b]pyridazines, imidazo[1,2-a[pyrimidines and imidazo[l,2-a]pyrazines. IC50 values (or percentage displacement) are reported and discussed for the displacement of [3H]diazepam from rat brain membrane by each of these compounds. The imidazo[l,2-a[pyridines were generally slightly less potent than the imidazo[l,2- b]pyridazines but considerably more potent than the corresponding imidazo[1,2-a]pyrimidines or imidazo[1,2- a[pyrazines. Substitution of a 2-aryl group by a 2-alkyl group in imidazo[l,2- b]pyridazines led to a significant loss of activity.

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. XI. Syntheses and Central Nervous System Activities of Some 6-(N-Benzyl-N-methylamino)-3-methoxy-2-phenyl(and substituted phenyl)imidazo[1,2-b]pyridazines

1992 ◽  
Vol 45 (4) ◽  
pp. 751 ◽  
Author(s):  
GB Barlin ◽  
LP Davies ◽  
SJ Ireland ◽  
JK Zhang
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rat Brain ◽  
Active Compound ◽  
Brain Membrane ◽  
Ic50 Values

Syntheses are reported for 196-(N-benzyl-N-methylamino )-3-methoxy-2-phenyl(and substituted phenyl or pyridinyl ) imidazo [1,2-b] pyridazines from 6-(N-benzyl-N-methylamino)pyridazin-3- amine 2-oxide. The ability of each of these compounds to displace [3H]diazepam from rat brain membrane preparations was measured and the IC50 values (or percentage displacements) are reported and discussed. 6-(N-Benzyl-N-methylamino )-3-methoxy-2-phenylimido[1,2-b]pyridine was about half as active as its 6-bemylamino analogue, and the most active compound was 6-(N-benzyl-N-methylamino )-2-(2'-fluorophenyl)-3-methoxyimido[1,2-b] pyridazine with IC50 9.8 nM.

Imidazo[1,2-b]pyridazines. X. Syntheses and Central Nervous System Activities of Some 3-(Acetamido, benzamido, substituted benzamido or dimethylamino)methyl-2-(phenyl or substituted phenyl)-6-(halogeno, alkylthio, alkoxy, phenylthio, phenoxy, benzylthio or benzyloxy)imidazo[1,2-b]pyridazines

1992 ◽  
Vol 45 (4) ◽  
pp. 731 ◽  
Author(s):  
GB Barlin ◽  
LP Davies ◽  
SJ Ireland ◽  
MML Ngu ◽  
JK Zhang
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rat Brain ◽  
Brain Membrane ◽  
Ic50 Values

Syntheses of some 3-( acetamido, benzamido , substituted benzamido or dimethylamino)methyl-2-(phenyl or substituted phenyl)-6( halogeno, alkylthio, alkoxy, phenylthio, phenoxy , benzylthio or benzyloxy ) imidazo [1,2-b] pyridazines from the 3-unsubstituted analogues are described. The IC50 values (or percentage displacements) are reported and discussed for the displacement of [3H]diazepam from rat brain membrane by each of these compounds. .The 3-benzamidomethyl compounds were generally the most active; of these, 3-benzamidomethyl-2-(3',4'-methylenedioxyphenyl)-6-methylthioimido[1,2-b] pyridazine showed outstanding activity with IC50 2 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 Lysosomal Storage Diseases-Regulating Neurodegeneration

2015 ◽  
Vol 9s2 ◽  
pp. JEN.S25475 ◽  
Author(s):  
Rob U. Onyenwoke ◽  
Jay E. Brenman
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Peripheral Nervous System ◽  
Pompe Disease ◽  
Lysosomal Storage Diseases ◽  
Cell Types ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
The Central Nervous System ◽  
Made In

Autophagy is a complex pathway regulated by numerous signaling events that recycles macromolecules and can be perturbed in lysosomal storage diseases (LSDs). The concept of LSDs, which are characterized by aberrant, excessive storage of cellular material in lysosomes, developed following the discovery of an enzyme deficiency as the cause of Pompe disease in 1963. Great strides have since been made in better understanding the biology of LSDs. Defective lysosomal storage typically occurs in many cell types, but the nervous system, including the central nervous system and peripheral nervous system, is particularly vulnerable to LSDs, being affected in two-thirds of LSDs. This review provides a summary of some of the better characterized LSDs and the pathways affected in these disorders.

Imidazo[1,2-b]pyridazines. XIV. Syntheses and Central Nervous System Activities of Some 6-(Methoxy-, dimethoxy-, methylenedioxy-, chloro- and fluoro-)-3-alkoxy-2-phenyl(and substituted phenyl)imidazo[1,2-b]pyridazines

1993 ◽  
Vol 46 (3) ◽  
pp. 353 ◽  
Author(s):  
GB Barlin ◽  
LP Davies ◽  
SJ Ireland ◽  
JK Zhang
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rat Brain ◽  
Brain Membrane ◽  
Ic50 Values

Syntheses are reported for 28 new 3-alkoxy-6-(3′-methoxy-,3′,4′-dimethoxy, 3′,4′-methylene-dioxy-, 2′- and 4′-chloro- and 4′-fluoro-benzylamino)-2-phenyl(and substituted phenyl) imidazo -[1,2-b] pyridazines from the corresponding 6-substituted pyridazin-3-amine 2-oxides with α- bromoacetophenones, followed by alkylation of the intermediate 3-hydroxyimidazo[1,2-b] pyridazines. In tests of the ability of these compounds to displace [3H]diazepam from rat brain membrane, 3-(2′-ethoxyethoxy)-6(3′-methoxybenzylamino)-2-phenyl- and 6(3′,4′-methylenedioxybenzylamino )-2-(3″,4″-methylenedioxyphenyl)-3-methoxy-imidazo[1,2-b] pyridazine bound most strongly, with IC50 values of 1nM.

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