2-(oxadiazolyl)- and 2-(thiazolyl)imidazo[1,2-a]pyrimidines as agonists and inverse agonists at benzodiazepine receptors.
Oxadiazoles, like the benzoyl group in a series of imidazo[1,2-a]pyrimidines, have been found to be metabolically stable alternatives to ester groups in benzodiazepine-receptor ligands. This change has lead to a number of compounds which bind to the receptors and which exhibit potent agonist activity in a food-motivated conflict test thought to predict anxiolytic properties. Compounds 4, 5, and 13 were equipotent with chlordiazepoxide but showed little or no myorelaxant effects. Replacing the oxadiazole group by thiazole gave compounds such as 23 which binds to the benzodiazepine receptor but exhibits the intrinsic activity of a partial inverse agonist in vivo.
Tully
W R
WR
Roussel Laboratories Ltd., Wiltshire, U.K.
Gardner
C R
CR
Gillespie
R J
RJ
Westwood
R
R
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D005442:Flumazenil / Q000378:metabolism / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D007093:Imidazoles; D010069:Oxadiazoles; D011743:Pyrimidines; D011963:Receptors, GABA-A; D005442:Flumazenil; C060714:divaplon