title: High affinity central benzodiazepine receptor ligands. Part 3: insights into the pharmacophore and pattern recognition study of intrinsic activities of pyrazolo[4,3-c]quinolin-3-ones.
abstract: Novel 2-phenyl-2,5-dihydropyrazolo[4,3-c]quinolin-3-(3H)-ones (PQs) endowed with high affinity for central benzodiazepine receptor (BzR) were synthesized. In particular, 9-fluoro-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (2(2)) showed binding affinity in the subnanomolar concentration range and proved to be in vitro a potent antagonist. This finding allowed the nature of the hydrogen bonding receptor site H(2) to be established, as located between the N-1 nitrogen of the PQ nucleus and the ortho position of the N-2-aryl group. [35S]tert-Butylbicyclophosphorothionate ([35S]TBPS) binding assays and electrophysiological measurements of the effects on GABA-evoked Cl(-) currents at recombinant human alpha(1)beta(2)gamma(2)(L) GABA(A) receptors, expressed in Xenopus laevis oocytes, were used to assess the intrinsic activities of a large series of PQs. With the aim of extracting discriminant information and distinguishing BzR ligands with different profiles of efficacy, 51 PQ derivatives, including full and partial agonists, antagonists, and inverse agonists, were analyzed in a multidimensional chemical descriptor space, defined by the lipophilicity parameter CLOG P and 3-D molecular WHIM descriptors, by means of principal component analysis, k-nearest neighbors (k-NN) method, and linear discriminant analysis (LDA). The classification methods were applied to subsets of pairs of efficacy classes, and lipophilicity and 3-D size descriptors were detected as the discriminant variables by a stepwise linear discriminant analysis. LDA proved to be superior to k-NN, especially in classifying PQ ligands (60-84% of success in prediction ability) into categories of efficacies which were contiguous and quite overlapped in the hyperspace of variables.
authors: Dipartimento Farmaco Chimico, Università degli Studi, Via E. Orabona 4, I-70125, Bari, Italy.
authors: Andrea
authors: A
authors: Carotti
authors: Cosimo
authors: C
authors: Altomare
authors: Luisa
authors: L
authors: Savini
authors: Luisa
authors: L
authors: Chiasserini
authors: Cesare
authors: C
authors: Pellerano
authors: Maria P
authors: MP
authors: Mascia
authors: Elisabetta
authors: E
authors: Maciocco
authors: Fabio
authors: F
authors: Busonero
authors: Manuel
authors: M
authors: Mameli
authors: Giovanni
authors: G
authors: Biggio
authors: Enrico
authors: E
authors: Sanna
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D005445:Flunitrazepam / Q000378:metabolism; D018757:GABA Modulators / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015363:Quinolones / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018757:GABA Modulators; D008024:Ligands; D015363:Quinolones; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate