PRESYNAPTIC CHOLINERGIC MODULATORS AS POTENT COGNITION ENHANCERS AND ANALGESIC DRUGS .2. 2-PHENOXY-ALKANOIC, 2-(PHENYLTHIO)-ALKANOIC, AND 2-(PHENYLAMINO)ALKANOIC ACID-ESTERS

Further modifications of the leads ((R)-(+)-hyoscyamine and (p-chlorop henyl)propionic acid alpha-tropanyl eater), which show analgesic and n ootropic activities as a consequence of increased central presynaptic ACh release, are reported. 2-Phenoxy- and 2-(phenylthio)alkanoic acid esters showed the best results. Several members of these classes posse ss analgesic properties which are comparable to that of morphine and a t the same time are able to reverse dicyclomine-induced amnesia. Confi rmation was found that the mechanism of action is due to an increase i n ACh release at central muscarinic synapses and that both auto- and h eteroreceptors controlling ACh release are very likely involved. Accor ding to the results obtained with (R)-(+)-hyoscyamine, analgesic activ ity is stereochemistry dependent, since the R-(+)-enantiomers are alwa ys more efficacious than the corresponding S-(-)-ones. On, the basis o f their potency and acute toxicity, compounds (+/-)-28 (SM(21)) and (/-)-42 (SM(32)) were selected for further study.