title: The influence of 5-HT(2A) activity on a 5-HT(2C) specific in vivo assay used for early identification of multiple acting SERT and 5-HT(2C) receptor ligands.
abstract: As a result of our exploratory programme aimed at elaborating dually acting compounds towards the serotonin (5-HT) transporter (SERT) and the 5-HT2C receptor a novel series of 3-amino-1-phenylpropoxy substituted diphenylureas was identified. From that collection two promising compounds (2 and 3) exhibiting highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) induced hypomotility in mice. In further pursuance of that objective (2-aminoethyl)(benzyl)sulfamoyl diphenylureas and diphenylpiperazines have also been elaborated. Herein we report the synthesis of potent multiple-acting compounds from this new class. However, when two optimized representatives (6 and 14) possessing the desired in vitro profile were tested neither reduced the motor activity of mCPP treated animals. Comparative albeit limited in vitro structure-activity relationship (SAR) analysis and detailed in vivo studies are discussed and explanation for their intricate behaviour is proposed.
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Olivér
authors.initials: O
authors.lastname: Éliás
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Nógrádi
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Domány
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szakács
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Kóti
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Szántay
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Ákos
authors.initials: Á
authors.lastname: Tarcsay
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, PO Box 286, H-1519, Hungary.
authors.forename: György M
authors.initials: GM
authors.lastname: Keserű
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Anikó
authors.initials: A
authors.lastname: Gere
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Dalma
authors.initials: D
authors.lastname: Kurkó
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Kolok
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Némethy
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kapui
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Hellinger
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Mónika
authors.initials: M
authors.lastname: Vastag
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Sághy
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Rita
authors.initials: R
authors.lastname: Kedves
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Nagyvárad tér 4, H-1089, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Gyertyán
mesh_terms: D000818:Animals; D006801:Humans; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010539:Permeability / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry* / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry* / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; C015068:1-(3-chlorophenyl)piperazine
keywords: 5-HT(2C) antagonist; Designed multiple ligand (DML); Polypharmacology; Serotonin antagonist and reuptake inhibitor (SARI); Serotonin reuptake inhibitor (SRI)