title: Novel selective and partial agonists of 5-HT3 receptors. Part 1. Synthesis and biological evaluation of piperazinopyrrolothienopyrazines.
abstract: A series of piperazinopyrrolo[1,2-a]thieno[3,2-e]- and -[2,3-e]pyrazine derivatives were prepared and evaluated in order to determine the necessary requirements for high affinity on the 5-HT3 receptors and high selectivity versus other 5-HT receptor subtypes. Various substitutions on the piperazine and the thiophene ring of the pyrrolothienopyrazine moieties were systematically explored as well as replacement of the piperazine by other cyclic amines. The best compounds are in the nanomolar range of affinity of 5-HT3 receptors with high to very high selectivity (up to 10,000 for 14b). These high-affinity compounds have in common a benzyl- or allylpiperazine substituent with no substitutions on the thiophene ring. Five of these compounds (1a, 4b, 13a,b, and 14b) have been evaluated on the Von Bezold-Jarisch reflex and were characterized as partial agonists. One of them, 13a, has shown in vivo at very low dose a potent anxiolytic-like activity in the light/dark test.
authors.affiliation: Center d'Etudes et de Recherche sur le Médicament de Normandie, Université de Caen, France.
authors.forename: S
authors.initials: S
authors.lastname: Rault
authors.forename: J C
authors.initials: JC
authors.lastname: Lancelot
authors.forename: H
authors.initials: H
authors.lastname: Prunier
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: B
authors.initials: B
authors.lastname: Guardiola-Lemaitre
authors.forename: M
authors.initials: M
authors.lastname: Hamon
mesh_terms: D000818:Animals; D002417:Cattle; D002831:Choroid Plexus / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013552:Swine
chemical_list: D011719:Pyrazines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists