Synthesis and cholinergic properties of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine.

The histaminergic H2 antagonist, ranitidine, has also been found to significantly inhibit acetylcholinesterase (AChE) in vitro. In an effort to develop novel, nonquaternary AChE inhibitors capable of penetrating into the CNS and alleviating the cholinergic deficit characteristic of Alzheimer's disease, a series of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine has been synthesized. All compounds were evaluated for human erythrocyte AChE inhibitory activity and compared to ranitidine, physostigmine, and tetrahydro-9-aminoacridine (THA). The most active AChE inhibitors were N,N'-disubstituted derivatives of 2-nitro-1,1-ethenediamine and 4,6-dinitro-1,3-benzenediamine, with compound 8 demonstrating activity greater than physostigmine. Deletion of the diaminonitroethene group in a series of alkyl and aryl bis-thioethers, yielded a number of slightly less active compounds, comparable in potency to THA. The 13 most active AChE inhibitors all demonstrated a more selective inhibition of AChE, as opposed to butyrylcholinesterase inhibition, than did THA. Compounds 3 and 22 were equally active to THA in potentiating rat ileal contractions. Binding studies demonstrated M1 and M2 cholinergic receptor affinities slightly greater than or equal to THA. Differential receptor binding studies showed compound 12 resembled THA in agonist/antagonist activity. Compounds 11-13 significantly elevated mouse brain acetylcholine levels, when administered at 80% of their approximate lethal doses, but were less active than THA or physostigmine.

Overflow movements and cognitive, motor and behavioural disturbance: a normative study of girls.

This study established norms for overflow movements of girls on the Modified Fog Test (MFT) of neurological function and investigated the relationship between high levels of overflow and behavioural and cognitive measures. 193 girls aged seven to 10 years, from suburban and inner-city areas, were examined for overflow, co-ordination and handedness, and completed cognitive and reading tests. Teachers' assessments of performance and behaviour at school were obtained and the parents of 147 girls were interviewed about developmental history, psychosocial situation and current behaviour. As predicted, there was a highly significant reduction in the amount of overflow with increasing age. Left-handed girls showed more overflow on the right side, in contrast to right- and mixed-handed girls. Girls in a combined group of 'poor performers' on the MFT were significantly more likely to show behaviour problems at school, and to be judged poor scholastically. They had significantly lower reading scores, were judged poor at handwriting and school sport, and scored lower on the Gubbay clap and catch task.