title: Synthesis and structure-activity relationship studies in translocator protein ligands based on a pyrazolo[3,4-b]quinoline scaffold.
abstract: As a further development of our large program focused on the medicinal chemistry of translocator protein [TSPO (18 kDa)] ligands, a new class of compounds related to alpidem has been designed using SSR180575, emapunil, and previously published pyrrolo[3,4-b]quinoline derivatives 9 as templates. The designed compounds were synthesized by alkylation of the easily accessible 4-methyl-2-phenyl-1H-pyrazolo[3,4-b]quinolin-3(2H)-one derivatives 13-15 with the required bromoacetamides. Along with the expected 2-(4-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazolo[3,4-b]quinolin-1-yl)acetamide derivatives 10, 2-(4-methyl-3-oxo-2-phenyl-2H-pyrazolo[3,4-b]quinolin-9(3H)-yl)acetamide isomers 11 were isolated and characterized. The high TSPO affinity shown by new pyrazolo[3,4-b]quinoline derivatives 10 and especially 11 leads the way to further expand the chemical diversity in TSPO ligands and provides new templates and structure-affinity relationship data potentially useful in the design of new anxiolytic and neuroprotective agents.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy. cappelli@unisi.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.forename: Giulia
authors.initials: G
authors.lastname: Bini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Valenti
authors.forename: Germano
authors.initials: G
authors.lastname: Giuliani
authors.forename: Marco
authors.initials: M
authors.lastname: Paolino
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordani
authors.forename: Luigi Piero
authors.initials: LP
authors.lastname: Stasi
authors.forename: Francesco
authors.initials: F
authors.lastname: Makovec
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Concas
authors.forename: Patrizia
authors.initials: P
authors.lastname: Porcu
authors.forename: Giovanni
authors.initials: G
authors.lastname: Biggio
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D020422:Mononeuropathies / Q000188:drug therapy; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; C463819:Bzrp protein, mouse; D002352:Carrier Proteins; D008024:Ligands; D011720:Pyrazoles; D011804:Quinolines; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C069997:Tspo protein, rat