SYNTHESIS AND CHOLINERGIC PROPERTIES OF BIS[[(DIMETHYLAMINO)METHYL]FURANYL]ANALOGUES OF RANITIDINE

The histaminergic H-2 antagonist, ranitidine, has also been found to s ignificantly inhibit acetylcholinesterase (AChE) in vitro. In an effor t to develop novel, nonquaternary AChE inhibitors capable of penetrati ng into the CNS and alleviating the cholinergic deficit characteristic of Alzheimer's disease, a series of bis[[(dimethylamino)methyl]furany l] analogues of ranitidine has been synthesized. All compounds were ev aluated 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-n itro-1,1-ethenediamine and 4,6-dinitro-1,3-benzenediamine, with compou nd 8 demonstrating activity greater than physostigmine. Deletion of th e diaminonitroethene group in a series of alkyl and aryl bis-thioether s, yielded a number of slightly less active compounds, comparable in p otency to THA. The 13 most active AChE inhibitors all demonstrated a m ore selective inhibition of AChE, as opposed to butyrylcholinesterase inhibition, than did THA. Compounds 3 and 22 were equally active to TH A in potentiating rat ileal contractions. Binding studies demonstrated M1 and M2 cholinergic receptor affinities slightly greater than or eq ual to THA. Differential receptor binding studies showed compound 12 r esembled THA in agonist/antagonist activity. Compounds 11-13 significa ntly elevated mouse brain acetylcholine levels, when administered at 8 0% of their approximate lethal doses, but were less active than THA or physostigmine.