NOVEL TACRINE ANALOGS FOR POTENTIAL USE AGAINST ALZHEIMERS-DISEASE - POTENT AND SELECTIVE ACETYLCHOLINESTERASE INHIBITORS AND 5-HT UPTAKE INHIBITORS

Several novel analogues of tacrine have been synthesized and tested fo r their ability to inhibit acetylcholinesterase, butyrylcholinesterase , and neuronal uptake of 5-HT (serotonin) and noradrenaline. Changes i n the size of the carbocyclic ring of tacrine produced modest potency against cholinesterase enzymes. Addition of a fourth ring resulted in compounds with marked selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase (BChE): e.g. 6-amino-4,5-benzo-5H-cyclopenta[1, 2-b]-quinoline (14a) had an IC50 of 0.35 mu M against AChE and 3.1 mu M against BChE. Some tetracyclic compounds are 100-400 times more acti ve than tacrine as inhibitors of neuronal uptake of serotonin, in part icular 13-amino-6,7-dihydro-5H-benzo[3 ,4]cyclohepta[1,2-b]quinoline ( 18), which had an IC50 of 20 nM. These compounds would be expected to facilitate both cholinergic and monoaminergic transmission. They shoul d be worth investigating in models of memory impairment.