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.
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.
Allen
M S
MS
Department of Chemistry, University of Wisconsin-Milwaukee 53201.
Skolnick
P
P
Cook
J M
JM
D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D005445:Flunitrazepam / Q000378:metabolism; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D008024:Ligands; D008956:Models, Chemical; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007546:Isoquinolines; D008024:Ligands; D011720:Pyrazoles; D015363:Quinolones; D011963:Receptors, GABA-A; D005445:Flunitrazepam