Synthesis and structure-activity relationships of a series of anxioselective pyrazolopyridine ester and amide anxiolytic agents.
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 by 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.
Bare
T M
TM
Department of Medicinal Chemistry, ICI Pharmaceuticals Group, Wilmington, Delaware 19897.
McLaren
C D
CD
Campbell
J B
JB
Firor
J W
JW
Resch
J F
JF
Walters
C P
CP
Salama
A I
AI
Meiners
B A
BA
Patel
J B
JB
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D000577:Amides; D014151:Anti-Anxiety Agents; D004952:Esters; D011720:Pyrazoles; D011725:Pyridines; C056562:ICI 190622