Synthesis and structure-activity relationships of a series of anxioselective pyrazolopyridine ester and amide anxiolytic agents

Article abstract of DOI:10.1021/jm00132a011

A series of 1-substituted 4-amino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid esters and amides were synthesized and screened for anxiolytic activity in the shock-induced suppression of drinking (SSD) test. The compounds were also tested for their ability to displace [³H]flunitrazepam (FLU) from brain benzodiazepine (BZ) binding sites. Many compounds were active in these screens and, additionally, demonstrated a selectivity for the type 1 BZ (BZ₁) receptor over the type 2 BZ (BZ₂) receptor as indicated by Hill coefficients significantly less than unity and analysis of [³H]FLU binding results from different brain regions. Based on the results of structure-activity studies of these compounds, a hypothesis was proposed to explain the structural features necessary for optimal interaction with brain BZ receptors. A detailed pharmacological evaluation of one of the most potent behaviorally active compounds (27) demonstrated it to be BZ₁ selective; also, in comparison to diazepam, 27 showed minimal sedative and alcohol interactive properties at therapeutically effective doses.