title: Design, synthesis, and preliminary pharmacological evaluation of a set of small molecules that directly activate gi proteins.
abstract: Heterotrimeric G proteins play a pivotal role in the communication of cells with the environment. G proteins are stimulated by cell surface receptors (GPCR) that catalyze the exchange of GDP, bound to Galpha subunit, with GTP and can per se be the target of drugs. Based on the structure of two nonpeptidic modulators of Gi proteins, a series of new molecules characterized by a long hydrophobic chain and at least two nitrogen atoms protonated at physiological pH was designed. The compounds were tested for their ability to stimulate binding of GTPgammaS to recombinant Gi proteins. Gi activation properties were also evaluated by inhibition of adenylyl cyclase activity in intact lymphocytes. Most compounds were able to stimulate GTPgammaS binding and to inhibit cAMP production at micromolar doses. Among the active compounds, 34 showed good efficacy and was the most potent compound studied, particularly on alpha(o) subtype; its regioisomer, 36, was the most efficacious one. Compound 7 showed also an interesting profile as it showed selectivity toward the alpha(o) subtype, in both efficacy and potency. Some of the compounds synthesized and found to be active may be useful leads to develop more potent and selective Gi protein modulators.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via U. Schiff 6, I-50019 Sesto Fiorentino (FI), Italy. dina.manetti@unifi.it
authors.forename: Dina
authors.initials: D
authors.lastname: Manetti
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Dei
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Galeotti
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.forename: Maria Novella
authors.initials: MN
authors.lastname: Romanelli
authors.forename: Serena
authors.initials: S
authors.lastname: Scapecchi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Teodori
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pacini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bartolini
authors.forename: Fulvio
authors.initials: F
authors.lastname: Gualtieri
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D010880:Piperidines; D011994:Recombinant Proteins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases