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. 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.

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. XIX. Syntheses and Central Nervous System Activities of Some 6-Arylthio(aryloxy and alkylthio)-3-(acetamidomethyl, benzamidomethyl, methoxy and unsubstituted)-2-arylimidazo[1,2-b]pyridazines

1996 ◽  
Vol 49 (4) ◽  
pp. 443 ◽  
Author(s):  
GB Barlin ◽  
LP Davies ◽  
SJ Ireland
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rat Brain ◽  
Active Compound ◽  
Binding Ability ◽  
Brain Membranes ◽  
Rat Brain Membranes

Some 6-arylthio( aryloxy and alkylthio )-3-( acetamidomethyl , benzamidomethyl, methoxy and unsubstituted )-2-arylimidazo[1,2-b] pyridazines have been prepared and examined for their ability to displace [3H]diazepam from rat brain membranes. The most active compound was 3-acetamidomethyl-2-(3',4'-methylenedioxyphenyl)-6-phenylthioimidazo[1,2-b] pyridazine with IC50 4.4 nM. The 3-acylaminomethyl-6-(2- and 3-methoxyphenylthio)-2-phenylimidazo[1,2-b] pyridazines proved less active than their 6-phenylthio analogues, and larger substituents at the 2- and 6-positions markedly decreased binding. Significant differences in binding ability have been observed between 3-acylaminomethyl-2-aryl-6-phenylthioimidazo[1,2-b] pyridazines and the corresponding imidazo [1,2-a]pyridines.

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. 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. 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. V. Syntheses and Central Nervous Activities of Some 3-Alkoxy-6-benzylthio(substituted benzylthio and Other phenylalkylthio)-2-phenyl(and substituted phenyl)imidazo[1,2-b]pyridazines

1989 ◽  
Vol 42 (7) ◽  
pp. 1133 ◽  
Author(s):  
GB Barlin ◽  
LP Davies ◽  
SJ Ireland ◽  
MML Ngu
Keyword(s):  
Rat Brain ◽  
Aminobutyric Acid ◽  
Lc50 Value ◽  
Brain Membranes ◽  
Rat Brain Membranes ◽  
Standard Assay ◽  
Assay Conditions

Syntheses are reported for a number of 3-alkoxy-6-benzylthio(substituted benzylthio and other phenylalkylthio )-2-phenyl(and substituted phenyl)imidazo[l,2-b]pyridazines. These compounds were then examined for their ability to displace 3H-diazepam from rat brain membranes. In preliminary tests, in the presence of 100 �m γ- aminobutyric acid (GABA) and under standard assay conditions (see Experimental), 6-benzylthio-3-methoxy-2-phenylimidazo[l,2- b]pyridazine gave an lC50 value of 25nM (IC50 for unlabelled diazepam is 4.3 nM ); its 6-(m- aminophenyl ), 6-(p- aminophenyl ) and 6-(m- nitrophenyl ) analogues gave values of 15, 9 and 8 nM respectively.

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