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

Article abstract of DOI:10.1021/jm00080a024

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 >> 2 μM) 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 (β-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 β-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.