A new cognition-enhancing agent, (R)-(-)-1-(benzo[b]thiophen-5-yl)- 2-[2-(N,N-diethylamino)ethoxy]ethanol hydrochloride. Effects on memory impairment in rats generated by cerebral embolization and basal forebrain lesions.

The title compound (T-588) has been evaluated for its ameliorating effect on memory impairment generated by cerebral embolization and by a basal forebrain (BF) lesion in male Wistar rats. The memory and learning deficits induced by injection of carbon-microspheres into the internal carotid artery were significantly improved by T-588 at oral dose of 3-10 mg/kg, as determined by an active avoidance response assay, whereas the reference drugs (tacrine, idebenone and indeloxazine) proved almost inactive in the same assay procedure. As far as the embolization was concerned, a significant decrease in cerebral acetylcholine and monoamines was observed. The effect on the memory impairment caused by an electrolytic lesion of the BF was assessed by a passive avoidance task. T-588 exhibited a bell-shaped dose-response curve and was most active at 1 mg/kg (oral dose), while tacrine showed equal activity at 10 mg/kg.

Studies on cognitive enhancing agents. I. Antiamnestic and antihypoxic activities of 2-dimethylaminoethyl ethers and related compounds.

N-(2-Dimethylaminoethyl)carboxamide (1a-d), 2-dimethylaminoethyl alkyl ether (2a, b), and 2-dimethylaminoethyl 2-hydroxy-2-phenethyl ether (3a-c) and its amino and methylene analogues (3d, 4) have been screened for antiamnestic and antihypoxic activities in mice. A clear reversing effect on electroconvulsive shock-induced amnesia was found with 1a-d, 2a,b, and 2-dimethylaminoethyl 2-hydroxy-2-phenylethyl ether (3a). However, a protective effect against hypoxia was only observed with 3a. Compound 3a, which displayed the dual activity, was further investigated for ameliorating effect on CO2-induced memory impairment, and it was found to be more potent than indeloxazine and bifemelane. In addition, the acute toxicity of 3a in mice was significantly lower than that of tacrine, but its serum-to-brain penetration ability in rats was less than that of the reference drugs.

Studies on cognitive enhancing agents. II. Antiamnestic and antihypoxic activities of 1-aryl-2-(2-aminoethoxy)ethanols.

A series of 2-(2-aminoethoxy)-1-phenylethanols having a variety of N- and phenyl-substitution patterns as well as 5- and 6-membered heteroaryl counterparts of our prototype compound 1 (2-(2-dimethylaminoethoxy)-1-phenylethanol) have been prepared and evaluated for antiamnestic and antihypoxic activities. Compound 3b, the 3-methylphenyl analogue of 1, proved to be significantly more potent than 1 in reversing electroconvulsive shock-induced amnesia as well as CO2-induced learning-impairment in mice. It exhibited low acute toxicity in mice and afforded a greater brain/serum concentration ratio than 1 after oral administration to rats.

Studies on cognitive enhancing agents. III. Antiamnestic and antihypoxic activities of a series of 1-bicycloaryl-2-(omega-aminoalkoxy)ethanols.

2-(2-Aminoethoxy)-1-hydroxyethyl derivatives of bicyclic arenes (naphthalene, thianaphthene, benzofuran, and indole) were prepared and screened for antiamnestic (AA) and antihypoxic (AH) activities which were evaluated by measuring the reversing potency in electroconvulsion-induced amnesia and the protective effect against hypoxia, respectively, in mice. Compound 3o, 1-(benzo[b]thiophen-5-yl)-2- (2-diethylaminoethoxy)ethanol, showed the best AA and AH activity profile, being superior to our prototype compound, 2-(2-dimethylaminoethoxy)-1-phenylethanol (1). Elongation of the ethylene linkage in the side chain of 3o to 3- and 4-carbon moieties brought about a significant decrease in AH activity. Compound 3o was further investigated for its protective effect against CO2-induced memory impairment and for acute toxicity in mice. It is ten-fold more potent than tacrine in the amnesia-reversal assay and is considerably less toxic than tacrine.

Protective effect of R(-)-1-(benzo[b]thiophen-5-yl)- 2-[2-(N,N-diethylamino)ethoxy]ethanol hydrochloride (T-588), a novel cerebral activator, against experimental cerebral anoxia.

Effects of R(-)-1-(benzo[b]thiophen-5-yl)-2-[2- (N,N-diethylamino)ethoxy]ethanol hydrochloride (T-588) on normobaric hypoxia, histotoxic anoxia by KCN and complete ischemia by decapitation were investigated in mice. T-588 (30-100 mg/kg, p.o.) showed a significant and dose-dependent prolongation of the survival time in all of the models studied. Bifemelane (100-300 mg/kg, p.o.) was also protective against all the models. Tacrine was protective against hypoxia but had no effect on anoxia and ischemia. Imipramine was protective against anoxia, but shortened the survival time of hypoxic mice. It had no effect on ischemia. The anti-hypoxic effect of T-588 was completely inhibited by pretreatment with scopolamine (1 mg/kg, i.p.), while the anti-anoxic effect was partially inhibited. Its effect on the ischemia was not affected by scopolamine. Hypoxia decreased the cerebral contents of ATP, phosphocreatine and glucose and increased the contents of lactate in mice. T-588 had no effect on these changes. Bifemelane prolonged pentobarbital-induced sleeping time in mice with the doses inducing anti-anoxic action, but T-588 did not. These results suggest that the activation of the CNS cholinergic system is involved as one of the mechanisms for the anti-anoxic action of T-588.

Studies on monocyclic beta-lactam antibiotics. III. Synthesis and antibacterial activity of N-(aromatic heterocyclic substituted)azetidin-2-ones.

The relationship between structure and antibacterial activity among monocyclic beta-lactams having a pyridyl, pyrimidinyl, thiazolyl, imidazolyl, or a tetrazolyl group at N-1 position was investigated. N-(Tetrazol-5-yl)azetidin-2-ones were found to posses excellent activity.