title: Structure-activity relationships in 2,2-diphenyl-2-ethylthioacetic acid esters: unexpected agonistic activity in a series of muscarinic antagonists.
abstract: As a continuation of previous research on anticholinergic drugs derived from 2,2-diphenyl-2-ethylthioacetic acid, several 5,5-diphenyl-5-ethylthio-2-pentynamines (2-11) were synthetised and their antimuscarinic activity on M(1-4) receptor subtypes was evaluated by functional tests and binding experiments. One of the compounds obtained showed unexpected agonistic activity in functional experiments on M(2) receptors. Since the compound carried a phenylpiperazine moiety, other similar compounds (12-17) were prepared and found to be endowed with similar behaviour. These ligands, although possessing the bulky structure characterising muscarinic antagonists, display agonistic activity at M(2) subtypes while, as expected, behaving as antagonists on M(3) and M(4) subtypes. On M(1) subtypes, they show agonistic activity which, however, is not blocked by atropine. The peculiar pharmacological profile of these compounds is of interest for studying muscarinic receptor subtypes.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Universitá di Firenze, Via Gino Capponi 9, 50121 Firenze, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Scapecchi
authors.forename: G
authors.initials: G
authors.lastname: Marucci
authors.forename: R
authors.initials: R
authors.lastname: Matucci
authors.forename: P
authors.initials: P
authors.lastname: Angeli
authors.forename: C
authors.initials: C
authors.lastname: Bellucci
authors.forename: M
authors.initials: M
authors.lastname: Buccioni
authors.forename: S
authors.initials: S
authors.lastname: Dei
authors.forename: F
authors.initials: F
authors.lastname: Gualtieri
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: D000480:Alkynes / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013552:Swine; D014649:Vas Deferens / Q000378:metabolism
chemical_list: D000480:Alkynes; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D001285:Atropine