PRESYNAPTIC CHOLINERGIC MODULATORS AS POTENT COGNITION ENHANCERS AND ANALGESIC DRUGS .1. TROPIC AND 2-PHENYLPROPIONIC ACID-ESTERS

Previous studies have shown that (R)-(+)-hyoscyarnine has analgesic ac tivity as a consequence of increased ACh release following antagonism of central muscarinic autoreceptors. Since the enhancement of central cholinergic transmission could be beneficial for cognitive disorders, we manipulated (R)-(+)-hyoscyamine, synthesizing several derivatives o f tropic and 2-phenylpropionic acids, with the aim of obtaining drugs which are able to increase ACh release and consequently to show analge sic and nootropic activities. The results showed that several new comp ounds are indeed potent analgesics (with an analgesic efficacy compara ble to that of morphine) and that the most potent one ((+/-)-19, PG(9) ) also has remarkable cognition-enhancing properties. Our study confir med that the mechanism of action involves ACh release even if it is st ill unclear whether only muscarinic autoreceptors or, also, heterorece ptors are involved.