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

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-mu-M) 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 (H-1). Finally, the results from this work indicate that a simultaneous interaction at both hydrogen bond donor (H-1) and acceptor sites (A2) at BzR is required for high affinity binding of inverse agonists.