G. B. Barlin

Syntheses, pharmacological evaluation and molecular modelling of substituted 6-alkoxyimidazo[1,2-b]pyridazines as new ligands for the benzodiazepine receptor

Summary A series of 2,3-disubstituted-6-alkoxyimidazo[1,2-b]pyridazines has been synthesized and evaluated for in vitro affinity for the benzodiazepine receptor (BZR). 3-(Benzamidomethyl or substituted benzamidomethyl)-6-methoxy-2-(3,4-methylenedioxyphenyl)imidazo[1,2-b]pyridazines were found to be the most potent BZR ligands (eg, 4a, IC50 7 nM; 4e, IC50 14 nM; 4v, IC50 8 nM). Imidazo[1,2-b]pyridazines unsubstituted in the 3-position, or containing bulkier alkoxy groups in the 6-position, were found to bind less strongly to the BZR. Selected compounds from the series were identified from in vitro GABA-shift experiments as BZR agonists. Molecular modelling has been employed to identify the common pharmacophoric points of lipophilic and hydrogen bonding, ligand-receptor interaction and areas of steric hindrance for these substituted imidazo[1,2-b]pyridazines at the BZR.

Imidazo[1,2-b]pyridazines. XVII. Synthesis and central nervous system activity of some 6-(alkylthio and chloro)-3-(methoxy, unsubstituted and benzamidomethyl)-2-arylimidazo[1,2-b]pyridazines containing methoxy, methylenedioxy and methyl substituents.

Syntheses are reported for 6-( methylthio, ethylthio, propylthio, substituted benzylthio and chloro )-3-( methoxy, unsubstituted and benzamidomethyl )-2-arylimidazo[1,2-b] pyridazines containing methoxy, methylenedioxy and methyl groups attached to phenyl substituents . In tests of the ability of these compounds to displace [3H]diazepam from rat brain membranes, 3-methoxy-6-(3′,4′-methylenedioxybenzylthio)-2- (3′,4′-methylenedioxyphenyl) imidazo [1,2-b] pyridazine (IC50 1 nM) bound most strongly; methylenedioxy groups were beneficial to activity whereas polymethoxy or dimethyl substituents were generally detrimental.

Substituted imidazo[1,2-b]pyridazines: New compounds with activity at central and peripheral benzodiazepine receptors

A large range of substituted imidazo[1,2-b]pyridazines have been synthesized, and a number of potent ligands at central benzodiazepine (Bz) receptors on rat brain membranes have been identified in initial binding screens using [3H]diazepam. For those tested more extensively, binding studies conducted in the presence and absence of gamma-aminobutyric acid suggest that they were full receptor agonists. Some preliminary evidence was found suggesting some species selectivity, i.e. several of the compounds were more active in in vivo tests in rats than in mice. The agonist activity of these 2-phenyl (and substituted phenyl) imidazo[1,2-b]pyridazines is consistent with the model of Bz receptor ligands as proposed by Fryer [Raven Press, 1983, pp. 7-20]. Several compounds were identified which had more selective activity at peripheral-type (mitochondrial) Bz binding sites. Thus, substituted imidazo[1,2-b]pyridazines represent yet another class of low molecular mass compounds which have activity at Bz receptor sites.

Some Remembrances of D. J. Brown by a Colleague

Gordon B. Barlin (Ph.D. (ANU); D.Sc. (Sydney)) worked for approximately 40 years in the John Curtin School of Medical Research, ANU, on the syntheses of nitrogen heterocyclic compounds and the examination of their physico-chemical and biological properties, including tautomerism, kinetics of nucleophilic substitution, enhancement of anticancer activity by phleomycin, new potential antimalarials, and an extensive study of substituted imidazo[1,2-b]pyridazines for interaction with central and peripheral nervous system receptors.