Synthesis of novel 2-phenyl-2H-pyrazolo[4,3-c]isoquinolin-3-ols: topological comparisons with analogs of 2-phenyl-2,5-dihydropyrazolo[4,3-c]quinolin-3-(3H)-ones at benzodiazepine receptors

Abstract

Based on the topology of pyrazoloquinolinones 10-12, a series of 2-phenyl-2H-pyrazolo[4,3-c]isoquinolines 6a-d, 7a-d, 8, and 9 have been synthesized and evaluated for their ability to inhibit radioligand binding to benzodiazepine receptors (BzR). Modification of the hydrogen bonding donor and acceptor characteristics of the NH and C = O functionalities of the pyrazoloquinolinones 10-12 resulted in ligands with dramatically reduced affinities (IC50 much greater than 2 microM) for BzR. The low affinities of 6a-d, 7a-d, 8, and 9 are consistent with the involvement of the NH function present on diverse classes of inverse agonists (beta-carbolines, diindoles, and pyrazoloquinolinones) with a hydrogen bond acceptor site (A2) on the binding protein. Moreover, it supports the involvement of the carbonyl function of the pyrazoloquinolinones and the pyridine nitrogen atom of beta-carbolines and diindoles with a hydrogen bond donor site (H1). Finally, the results from this work indicate that a simultaneous interaction at both hydrogen bond donor (H1) and acceptor sites (A2) at BzR is required for high affinity binding of inverse agonists.

Pharmacophore/Receptor Models for GABAA/BzR Subtypes (α1β3γ2, α5β3γ2, and α6β3γ2) via a Comprehensive Ligand-Mapping Approach

“…Finally, the centroid of the phenyl moiety at position-2 was aligned in the lipophilic region L 1 of the pharmacophore/receptor model (Figure ). This alignment has been employed for ligands 118 − 129 in the present work and is in complete agreement with earlier modeling reported in this series. ,, …”

“…Pyrazoloquinolin-3-ones (CGS Series). The pyrazoloquinolines, discovered in the laboratories of Ciba-Geigy (the so-called CGS series), were found to bind to both DS and DI BzR sites (α1−6 isoforms). ,,, A wide range of pyrazoloquinolinones have been synthesized by a number of research groups to correlate the substitution pattern and structure with the intrinsic activity of a ligand. ,− Although many of the ligands are active in vivo as anxiolytic/anticonvulsant agents or as inverse agonists, the future for the original CGS series as clinical agents was limited due to the poor solubility of these ligands. However, the unique topology of their structure along with the potent affinity in vitro establishes them as excellent templates for the development of pharmacophore/receptor models. , The fit of the CGS series at the H 1 , H 2 , and L 1 descriptors of the pharmacophore/receptor models (α1−6 isoforms) for BzR is nearly perfect.…”

“…39,80,124,125 - A wide range of pyrazoloquinolinones have been synthesized by a number of research groups to correlate the substitution pattern and structure with the intrinsic activity of a ligand. 39,[124][125][126][127] Although many of the ligands are active in vivo as anxiolytic/anticonvulsant agents or as inverse agonists, the future for the original CGS series as clinical agents was limited due to the poor solubility of these ligands. However, the unique topology of their structure along with the potent affinity in vitro establishes them as excellent templates for the development of pharmacophore/receptor models.…”

“…Chemistry. The syntheses of the ligands employed in this study have been reported elsewhere. ,,,,− ,,,,,,,,,,,,,,, …”

3,5-Bis(trifluoromethyl)pyrazoles: A Novel Class of NFAT Transcription Factor Regulator

“…13 One of the more versatile intermediates for introducing functionality at C5 on the pyrazole was the condensation product of 4-nitrophenylhydrazine and the β-ketoester,ethyl4,4,4-trifluoroacetoacetate,whichisillustrated in Scheme 3. Although the C5 hydroxy analogues lacked activity, alkylation 14 or transformation to a halogen 15 produced some of the more biologically interesting analogues. The key intermediate was also accessed with S-methyl 4,4,4-trifluoro-3-oxothiobutyrate which additionally gave a limited amount of the C5 S-methyl ether.…”