title: Further structure-activity relationships in the series of tropanyl esters endowed with potent antinociceptive activity.
abstract: Several analogs of the alpha-tropanyl esters of 2-(4-chlorophenoxy)butyric acid (SM21) and 2-phenylthiobutyric acid (SM32), endowed with potent antinociceptive and cognition enhancing activity, were synthesized, aimed at obtaining more potent and safe drug candidates. Variation of the acyl moiety (4-11), as well as the conformational restriction of atropine to give the alpha-tropanyl ester of 2,3-dihydrobenzofurane-3-carboxylic acid (18), practically abolished activity. In the case of 18, the antimuscarinic activity was also severely affected by the conformation restrain. On the contrary, conformational restriction of phenoxybutyric and phenylthiobutyric acid derivatives to give the alpha-tropanyl ester of 2,3-dihydro-benzofurane-2-carboxylic acid and 2,3-dihydro-benzothiophene-2-carboxylic acid (12-17), afforded potent analgesic drugs that unfortunately were too toxic to be reliable drug candidates. A series of related esters of benzofurane-3-carboxylic acid (20-27) and benzothiophene-3-carboxylic acid (28) were also studied and found to be potent but toxic analgesics.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Scapecchi
authors.forename: A
authors.initials: A
authors.lastname: Giorgi
authors.forename: C
authors.initials: C
authors.lastname: Bellucci
authors.forename: S
authors.initials: S
authors.lastname: Dei
authors.forename: C
authors.initials: C
authors.lastname: Ghelardini
authors.forename: D
authors.initials: D
authors.lastname: Manetti
authors.forename: M N
authors.initials: MN
authors.lastname: Romanelli
authors.forename: E
authors.initials: E
authors.lastname: Teodori
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D018727:Muscarinic Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D011817:Rabbits; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D000700:Analgesics; D018727:Muscarinic Antagonists; D014326:Tropanes