title: Novel and selective partial agonists of 5-HT3 receptors. 2. Synthesis and biological evaluation of piperazinopyridopyrrolopyrazines, piperazinopyrroloquinoxalines, and piperazinopyridopyrroloquinoxalines.
abstract: In continuation of our previous work on piperazinopyrrolothienopyrazine derivatives, three series of piperazinopyridopyrrolopyrazines, piperazinopyrroloquinoxalines, and piperazinopyridopyrroloquinoxalines were prepared and evaluated as 5-HT3 receptor ligands. The chemical modifications performed within these new series led to structure-activity relationships regarding both high affinity and selectivity for the 5-HT3 receptors that are in agreement with those established previously for the pyrrolothienopyrazine series. The best compound (8a) obtained in these new series is in the picomolar range of affinity for 5-HT3 receptors with a selectivity higher than 10(6). Four of the high-affinity 5-HT3 ligands (8a, 15a,b, and 16d) were selected in both the pyridopyrrolopyrazine and the pyrroloquinoxaline series and were characterized in vitro and in vivo as agonists or partial agonists. Compound 8a was also evaluated in the light/dark test where it showed potential anxiolytic-like activity at very low doses per os.
authors.affiliation: Centre d'Etudes et de Recherche sur le Médicament de Normandie, Université de Caen, France.
authors.forename: H
authors.initials: H
authors.lastname: Prunier
authors.forename: S
authors.initials: S
authors.lastname: Rault
authors.forename: J C
authors.initials: JC
authors.lastname: Lancelot
authors.forename: M
authors.initials: M
authors.lastname: Robba
authors.forename: P
authors.initials: P
authors.lastname: Renard
authors.forename: P
authors.initials: P
authors.lastname: Delagrange
authors.forename: B
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: D H
authors.initials: DH
authors.lastname: Caignard
authors.forename: R
authors.initials: R
authors.lastname: Misslin
authors.forename: B
authors.initials: B
authors.lastname: Guardiola-Lemaitre
authors.forename: M
authors.initials: M
authors.lastname: Hamon
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000209:etiology; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D003624:Darkness; D005625:Frontal Lobe / Q000378:metabolism; D019791:Guanidine; D006146:Guanidines / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008027:Light; D008297:Male; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: C106586:6-(4-benzylpiperazino)pyrido(3,2-e)pyrrolo(1,2-a)pyrazine; D014151:Anti-Anxiety Agents; D006146:Guanidines; D011719:Pyrazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists; D019791:Guanidine