title: Presynaptic cholinergic modulators as potent cognition enhancers and analgesic drugs. 2. 2-Phenoxy-, 2-(phenylthio)-, and 2-(phenylamino)alkanoic acid esters.
abstract: Further modifications of the leads ((R)-(+)-hyoscyamine and (p-chlorophenyl)propionic acid alpha-tropanyl ester), which show analgesic and nootropic 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 possess analgesic properties which are comparable to that of morphine and at the same time are able to reverse dicyclomine-induced amnesia. Confirmation was found that the mechanism of action is due to an increase in ACh release at central muscarinic synapses and that both auto- and heteroreceptors controlling ACh release are very likely involved. According to the results obtained with (R)-(+)-hyoscyamine, analgesic activity is stereochemistry dependent, since the R-(+)-enantiomers are always more efficacious than the corresponding S-(-)-ones. On the basis of their potency and acute toxicity, compounds (+/-)-28 (SM21) and (+/-)-42 (SM32) were selected for further study.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Gualtieri
authors.forename: C
authors.initials: C
authors.lastname: Bottalico
authors.forename: A
authors.initials: A
authors.lastname: Calandrella
authors.forename: S
authors.initials: S
authors.lastname: Dei
authors.forename: M P
authors.initials: MP
authors.lastname: Giovannoni
authors.forename: S
authors.initials: S
authors.lastname: Mealli
authors.forename: M N
authors.initials: MN
authors.lastname: Romanelli
authors.forename: S
authors.initials: S
authors.lastname: Scapecchi
authors.forename: E
authors.initials: E
authors.lastname: Teodori
authors.forename: N
authors.initials: N
authors.lastname: Galeotti
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism*; D000698:Analgesia; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D003071:Cognition / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D011422:Propionates / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D014326:Tropanes / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000085:Acetates; D000700:Analgesics; D011422:Propionates; D014326:Tropanes; C087569:N-methyltropan-3-yl 2-(phenylthio)propionate; C087568:N-methyltropan-3-yl 2-(4-chlorophenoxy)propionate; D000109:Acetylcholine