title: 2-Arylpyrazolo[1,5-a]pyrimidin-3-yl acetamides. New potent and selective peripheral benzodiazepine receptor ligands.
abstract: A new class of N,N-diethyl-(2-arylpyrazolo[1,5-a]pyrimidin-3-yl)acetamides (3f-y), as azaisosters of Alpidem, was prepared following a novel synthetic method and their affinities for both the peripheral (PBR) and the central (CBR) benzodiazepine receptors were evaluated. Binding assays were carried out using both [3H]PK 11195 and [3H]Ro 5-4864 as radioligands for PBR, whereas [3H]Ro 15-1788 was used for CBR, in rat kidney and rat cortex, respectively. The tested compounds exhibited a broad range of binding affinities from as low as 0.76 nM to inactivity and most of them proved to be high selective ligands for PBR. The preliminary SAR studies suggested some of the structural features required for high affinity and selectivity; particularly the substituents on the pyrimidine moiety seemed to play an important role in PBR versus CBR selectivity. A subset of the highest affinity compounds was also tested for their ability to stimulate steroid biosynthesis in C6 glioma rat cells and some of these were found to increase pregnenolone formation with potency similar to Ro 5-4864 and PK 11195.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via G. Capponi 9, 50121, Firenze, Italy. silvia.selleri@unifi.it
authors.forename: S
authors.initials: S
authors.lastname: Selleri
authors.forename: F
authors.initials: F
authors.lastname: Bruni
authors.forename: C
authors.initials: C
authors.lastname: Costagli
authors.forename: A
authors.initials: A
authors.lastname: Costanzo
authors.forename: G
authors.initials: G
authors.lastname: Guerrini
authors.forename: G
authors.initials: G
authors.lastname: Ciciani
authors.forename: B
authors.initials: B
authors.lastname: Costa
authors.forename: C
authors.initials: C
authors.lastname: Martini
mesh_terms: D000081:Acetamides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D001665:Binding Sites; D002540:Cerebral Cortex / Q000378:metabolism; D002998:Clonazepam / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D005910:Glioma; D007425:Intracellular Membranes / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000081:Acetamides; D001570:Benzodiazepinones; D007546:Isoquinolines; D008024:Ligands; D011720:Pyrazoles; D011743:Pyrimidines; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam; D005442:Flumazenil; D002998:Clonazepam; C037850:PK 11195