Memory is dependent upon the function of cholinergic cells in the cortex and hippocampus of the forebrain. The cholinergic cells in the basal forebrain reside in three regions, the nucleus basalis of Meynert, the medial septal nucleus and the nucleus of the diagonal band. These cells are responsible for most, perhaps all, of the cholinergic innervation in the cortex and hippocampus. It is known that these three structures and that their respective pathways are important in memory. Additionally, it is known that in Alzheimer's dementia up to half of these neurons and their projections may be lost. By stimulating the remaining neurons it should be possible to recover some of the memory deficits in Alzheimer's dementia and other forms of memory loss, including Wernicke-Korsakoff syndrome.
Previous reports have indicated that agents with activity at the .gamma.-aminobutyric acid (GABA)-receptor complex when given in vivo modulate high affinity choline uptake (HACU) measured in vitro. It is thought that HACU measured in vitro reflects the activity of cholinergic neurons in vivo. Drugs which have a sedative or hypnotic activity have generally been found to depress cortical or hippocampal HACU. More recently, several studies, for example, those of Lorez, et al., Drug Devel. Res. 14, 359-362, 1988; Shih and Pugsley, Life Sci. 36, 2145-2152, 1985; Spignoli et al., Clin. Neuropharmacol. Supp. 3, 39-47, 1986; Nakahiro, M., et al., Br. J. Pharmacol. 95, 1303-1307, 1988, report that drugs which enhance cognition, e.g., pramiracetam, oxiracetam and pantoyl-GABA, stimulate cortical or hippocampal HACU after in vivo administration.
Another measure of cholinergic activity is the binding of the radioligand [.sup.3 H] hemicholinium-3, ([.sup.3 H] HC-3) which labels the carrier that mediates choline transport. Swann and Hewitt (Neuropharmacol. 27:611-615, 1988) have demonstrated that the B.sub.max of .sup.3 H HC-3 increases in parallel with HACU when cholinergic synaptosomes are stimulated. Therefore, the stimulation of [.sup.3 H] HC-3 binding in vitro after treatment with drugs in vivo is also a marker for increased cholinergic activity, predictive of enhanced cognition in treated animals.
Compounds of formula I wherein R.sub.2 represents C.sub.1-3 lower alkyl have previously been shown to have antidepressant activity, as disclosed, for example, in U.S. Pat. No. 4,775,688, issued Oct. 4, 1988, and in U.S. Pat. No. 4,912,095, issued Mar. 27, 1990. 5-(4-Chlorophenyl)-2,4-dimethyl-3H-1,2,4-triazole-3-thione, the compound of formula I wherein R.sub.2 and R.sub.4 both represent methyl, n is 1, and R represents chloro located in the 4-position of the phenyl substituent, is useful in the treatment of thrombocytosis and the prevention of thrombosis and hemorrhage resulting therefrom, as disclosed, for example, in U.S. Pat. No. 4,847,276, issued July 11, 1989.
The effects of known antidepressant drugs on cholinergic markers for activity such as high affinity choline uptake (HACU) or [.sup.3 H] hemicholinium-3 binding is not consistent. Garattini et al. (Psychopharmacol. 82:210-214, 1983) reported a weak effect of minaprine on striatal, cortical and hippocampal HACU after a 30 mg/kg. acute dose. However, other antidepressants such as amitriptyline (Hridina and Elson-Hartman, Neuropharmacol. 21:1349-53, 1982; and Goldman and Erickson, Neuropharmacol. 22:1215-1222, 1983) and imipramine, desipramine, iprindole, and viloxazine (Jones, Can. J. Physiol. Pharmacol. 59:392-396, 1981) had no effect on HACU after acute administration i.p. Therefore we can conclude that stimulation of cortical markers for cholinergic activity are not generally increased by antidepressant drugs.
Long term potentiation in the hippocampus is also widely regarded as a useful model for the physiological processes underlying the development of memory. It is known that many compounds that are known to enhance memory also augment the development of this long term potentiation in the hippocampus. Unfortunately, most of the known memory enhancing compounds also produce side effects which limit their therapeutic potential. Such side effects are not found with compounds of formula I.
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USPTO Backgrounds