title: Identification of novel NK1/NK3 dual antagonists for the potential treatment of schizophrenia.
abstract: During the lead optimization of NK(1)/NK(3) receptor antagonists program, a focused exploration of molecules bearing a lactam moiety was performed. The aim of the investigation was to identify the optimal position of the carbonyl and hydroxy methyl group in the lactam moiety, in order to maximize the in vitro affinity and the level of insurmountable antagonism at both NK(1) and NK(3) receptors. The synthesis and biological evaluation of these novel lactam derivatives, with potent and balanced NK(1)/NK(3) activity, were reported in this paper.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Neurosciences Centre of Excellence for Drug Discovery, Via Fleming 4, 37135 Verona, Italy. mariapia.catalani@inwind.it
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Catalani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Alvaro
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bernasconi
authors.forename: Ezio
authors.initials: E
authors.lastname: Bettini
authors.forename: Steven M
authors.initials: SM
authors.lastname: Bromidge
authors.forename: Jag
authors.initials: J
authors.lastname: Heer
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tedesco
authors.forename: Simona
authors.initials: S
authors.lastname: Tommasi
mesh_terms: D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007769:Lactams / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D007769:Lactams; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D018042:Receptors, Neurokinin-3