Pinna G

References (2)

Title : Multitarget-directed tricyclic pyridazinones as g protein-coupled receptor ligands and cholinesterase inhibitors - Pau_2015_ChemMedChem_10_1054
Author(s) : Pau A , Catto M , Pinna G , Frau S , Murineddu G , Asproni B , Curzu MM , Pisani L , Leonetti F , Loza MI , Brea J , Pinna GA , Carotti A
Ref : ChemMedChem , 10 :1054 , 2015
Abstract : By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A , adrenergic alpha1A , and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of alpha1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles.
ESTHER : Pau_2015_ChemMedChem_10_1054
PubMedSearch : Pau_2015_ChemMedChem_10_1054
PubMedID: 25924828

Title : The combination of huperzine A and imidazenil is an effective strategy to prevent diisopropyl fluorophosphate toxicity in mice - Pibiri_2008_Proc.Natl.Acad.Sci.U.S.A_105_14169
Author(s) : Pibiri F , Kozikowski AP , Pinna G , Auta J , Kadriu B , Costa E , Guidotti A
Ref : Proc Natl Acad Sci U S A , 105 :14169 , 2008
Abstract : Diisopropyl fluorophosphate (DFP) causes neurotoxicity related to an irreversible inhibition of acetylcholinesterase (AChE). Management of this intoxication includes: (i) pretreatment with reversible blockers of AChE, (ii) blockade of muscarinic receptors with atropine, and (iii) facilitation of GABA(A) receptor signal transduction by benzodiazepines. The major disadvantage associated with this treatment combination is that it must to be repeated frequently and, in some cases, protractedly. Also, the use of diazepam (DZP) and congeners includes unwanted side effects, including sedation, amnesia, cardiorespiratory depression, and anticonvulsive tolerance. To avoid these treatment complications but safely protect against DFP-induced seizures and other CNS toxicity, we adopted the strategy of administering mice with (i) small doses of huperzine A (HUP), a reversible and long-lasting (half-life approximately 5 h) inhibitor of AChE, and (ii) imidazenil (IMI), a potent positive allosteric modulator of GABA action selective for alpha(5)-containing GABA(A) receptors. Coadministration of HUP (50 microg/kg s.c., 15 min before DFP) with IMI (2 mg/kg s.c., 30 min before DFP) prevents DFP-induced convulsions and the associated neuronal damage and mortality, allowing complete recovery within 18-24 h. In HUP-pretreated mice, the ED(50) of IMI to block DFP-induced mortality is approximately 10 times lower than that of DZP and is devoid of sedation. Our data show that a combination of HUP with IMI is a prophylactic, potent, and safe therapeutic strategy to overcome DFP toxicity.
ESTHER : Pibiri_2008_Proc.Natl.Acad.Sci.U.S.A_105_14169
PubMedSearch : Pibiri_2008_Proc.Natl.Acad.Sci.U.S.A_105_14169
PubMedID: 18784370