title: Presynaptic cholinergic modulators as potent cognition enhancers and analgesic drugs. 1. Tropic and 2-phenylpropionic acid esters.
abstract: Previous studies have shown that (R)-(+)-hyoscyamine has analgesic activity 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 of tropic and 2-phenylpropionic acids, with the aim of obtaining drugs which are able to increase ACh release and consequently to show analgesic and nootropic activities. The results showed that several new compounds are indeed potent analgesics (with an analgesic efficacy comparable to that of morphine) and that the most potent one ((+/-)-19, PG9) also has remarkable cognition-enhancing properties. Our study confirmed that the mechanism of action involves ACh release even if it is still unclear whether only muscarinic autoreceptors or, also, heteroreceptors are involved.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Gualtieri
authors.forename: G
authors.initials: G
authors.lastname: Conti
authors.forename: S
authors.initials: S
authors.lastname: Dei
authors.forename: M P
authors.initials: MP
authors.lastname: Giovannoni
authors.forename: F
authors.initials: F
authors.lastname: Nannucci
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: L
authors.initials: L
authors.lastname: Fanfani
authors.forename: C
authors.initials: C
authors.lastname: Ghelardini
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000698:Analgesia; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D018727:Muscarinic Antagonists; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D014326:Tropanes / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000700:Analgesics; D018727:Muscarinic Antagonists; D010666:Phenylpropionates; D011976:Receptors, Muscarinic; D014326:Tropanes; C087567:N-methyltropan-3-yl 2-(4-bromophenyl)propionate; D000109:Acetylcholine