title: Design, synthesis and binding properties of novel and selective 5-HT3 and 5-HT4 receptor ligands.
abstract: This work reports the synthesis and the binding tests on the 5-HT3 and 5-HT4 receptors of new thienopyrimidopiperazine and piperazinylacylaminodimethylthiophene derivatives, in order to identify potent and selective ligands for each receptor. The 3-amino-2-(4-benzyl-1-piperazinyl)-5,6-dimethyl-thieno[2,3-d]pyrimidin-4(3H)-one derivative 28 showed the highest affinity and selectivity for the 5-HT3 over the 5-HT4 receptor (5-HT3 Ki=3.92 nM, 5-HT4 not active), whereas the 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butanoylamino]-4,5-dimethyl-3-thiophenecarboxylic acid ethyl ester (41) showed the highest affinity and selectivity for the 5-HT4 over the 5-HT3 receptor (5-HT4 Ki=81.3 nM, 5-HT3 not active). Conformational analyses were carried out on the compounds of the piperazinylacylaminodimethylthiophene series (39-42) taking compound 41 as the template.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, viale Andrea Doria, 6, Ed. 2 Città Universitaria, I-95125, Catania, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Modica
authors.forename: M
authors.initials: M
authors.lastname: Santagati
authors.forename: S
authors.initials: S
authors.lastname: Guccione
authors.forename: F
authors.initials: F
authors.lastname: Russo
authors.forename: A
authors.initials: A
authors.lastname: Cagnotto
authors.forename: M
authors.initials: M
authors.lastname: Goegan
authors.forename: T
authors.initials: T
authors.lastname: Mennini
mesh_terms: D000818:Animals; D006224:Cricetinae; D015195:Drug Design; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C434627:2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butanoylamino)-4,5-dimethyl-3-thiophenecarboxylic acid ethyl ester; C434628:3-amino-2-(4-benzyl-1-piperazinyl)-5,6-dimethyl-thieno(2,3-d)pyrimidin-4(3H)-one; D008024:Ligands; D010879:Piperazines; D011743:Pyrimidines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D013876:Thiophenes; D044422:Receptors, Serotonin, 5-HT4