Imidazo[1,2-b]Pyridazines. VIII. Syntheses and Central Nervous System Activities of Some 6-Benzylamino (and methoxybenzylamino)-3-methoxy-2-phenyl(Substituted phenyl or pyridinyl)imidazo[1,2-b]pyridazines

1989 ◽  
Vol 42 (10) ◽  
pp. 1759 ◽  
Author(s):  
GB Barlin ◽  
LP Davies ◽  
MML Ngu
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Plasma Membrane ◽  
Rat Brain ◽  
Binding Activity ◽  
Ring System ◽  
Pyridazine Ring ◽  
Ic50 Values ◽  
Brain Plasma Membrane

Syntheses and IC50 values for the displacement of 3H-diazepam from rat brain plasma membrane are reported for a series of 6-benzylamino(and methoxybenzylamino )-3-methoxy-2-phenyl(substituted phenyl and pyridinyl )imidazo[l,2-b]pyridazines (and their 6-anilino and 6-phenethylamino analogues). The results are compared with those reported previously (by us) for the 6-chloro, 6-phenoxy, 6-benzylthio, and 6-benzyloxy compounds. In the imidazo[l,2-b]pyridazine ring system, 6-(o- and m- methoxybenzylamino ) groups were found to be beneficial to binding activity; eight compounds have been prepared with IC50 values less than 2 nM (cf. 3H-diazepam with IC50 of 4.2 nM ).2-(p-Aminopheny1)-3-methoxy- 6-(m- methoxybenzylamino )imidazo[1,2-b]pyridazine exhibited the highest activity with IC50 1.0 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. 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.

scholarly journals P-glycoprotein traffics from the nucleus to the plasma membrane in rat brain endothelium during inflammatory pain

2016 ◽  
Vol 36 (11) ◽  
pp. 1913-1928 ◽  
Author(s):  
Margaret E Tome ◽  
Joseph M Herndon ◽  
Charles P Schaefer ◽  
Leigh M Jacobs ◽  
Yifeng Zhang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Plasma Membrane ◽  
Endothelial Cell ◽  
Rat Brain ◽  
Inflammatory Pain ◽  
Central Nervous System Drug ◽  
P Glycoprotein

P-glycoprotein (PgP), a drug efflux pump in blood–brain barrier endothelial cells, is a major clinical obstacle for effective central nervous system drug delivery. Identifying PgP regulatory pathways that can be exploited clinically is critical for improving central nervous system drug delivery. We previously found that PgP activity increases in rat brain microvessels concomitant with decreased central nervous system drug delivery in response to acute peripheral inflammatory pain. In the current study, we tested the hypothesis that PgP traffics to the luminal plasma membrane of the microvessel endothelial cells from intracellular stores during peripheral inflammatory pain. Using immunofluorescence microscopy, we detected PgP in endothelial cell nuclei and in the luminal plasma membrane in control animals. Following peripheral inflammatory pain, luminal PgP staining increased while staining in the nucleus decreased. Biochemical analysis of nuclear PgP content confirmed our visual observations. Peripheral inflammatory pain also increased endothelial cell luminal staining of polymerase 1 and transcript release factor/cavin1 and serum deprivation response protein/cavin2, two caveolar scaffold proteins, without changing caveolin1 or protein kinase C delta binding protein/cavin3 location. Our data (a) indicate that PgP traffics from stores in the nucleus to the endothelial cell luminal membrane in response to peripheral inflammatory pain; (b) provide an explanation for our previous observation that peripheral inflammatory pain inhibits central nervous system drug uptake; and (c) suggest a novel regulatory mechanism for PgP activity in rat brain.

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. 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.

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.

Sign in / Sign up

Export Citation Format

Share Document