Benzodiazepine receptor binding activity of 9-(1-phenylethyl)purines.
Several alpha-methyl analogues of the 9-benzylpurines that bind to the benzodiazepine receptor (BZR) were synthesized and tested for BZR-binding activity. Although introduction of a m-amino group and an 8-bromo substituent gave an additive increase in BZR affinity with 9-(3-aminobenzyl)-8-bromo-6-(dimethylamino)-9H-purine (4), addition of an alpha-methyl group to 4 resulted in a loss in BZR affinity. This loss in affinity is apparently due to repulsive, steric interactions between the 8-bromo and 9-(1-phenylethyl) substituents, which results in a conformation that is not optimal for interaction with the BZR. Several compounds were tested on a modified Geller-Seifter conflict schedule, but none exhibited significant anxiolytic activity.
Kelley
J L
JL
Division of Organic Chemistry, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
McLean
E W
EW
Ferris
R M
RM
Howard
J L
JL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D003220:Conflict, Psychological; D003975:Diazepam / Q000378:metabolism; D007202:Indicators and Reagents; D007700:Kinetics; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001593:Benzyl Compounds; D007202:Indicators and Reagents; D011687:Purines; D011963:Receptors, GABA-A; D003975:Diazepam