Design, synthesis and binding properties of novel and selective 5-HT(3) and 5-HT(4) receptor ligands.
This work reports the synthesis and the binding tests on the 5-HT(3) and 5-HT(4) receptors of new thienopyrimidopiperazine and piperazinylacylaminodimethylthiophene derivatives, in order to identify potent and selective ligands for each receptor. The compound with higher affinity and selectivity for the 5-HT(3) over the 5-HT(4) receptor was the 3-amino-2-(4-benzyl-1-piperazinyl)-5,6-dimethyl-thieno[2,3-d]pyrimidin-4(3H)-one 28 (5-HT(3) K(i)=3.92 nM, 5-HT(4) not active), the compound with higher affinity and selectivity for the 5-HT(4) over the 5-HT(3) receptor was the 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butanoylamino]-4,5-dimethyl-3-thiophenecarboxylic acid ethyl ester 41 (5-HT(4) K(i)=81.3 nM, 5-HT(3) not active). Conformational analyses were carried out on the compounds of the piperazinylacylaminodimethylthiophene series (39-42) taking compound 41 as the template.
Dipartimento di Scienze Farmaceutiche, Università di Catania, viale A. Doria 6, 95125, Catania, Italy.
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Mennini
D000818:Animals; D015195:Drug Design; D006168:Guinea Pigs; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D011985:Receptors, Serotonin / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D018490:Serotonin Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
D008024:Ligands; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D018490:Serotonin Agents; D044422:Receptors, Serotonin, 5-HT4