"Peripheral-type" binding sites for benzodiazepines in brain: relationship to the convulsant actions of Ro 5-4864.
Previous studies have shown that Ro 5-4864 is a potent convulsant and increases the firing rate of substantia nigra zona reticulata neurons. The pharmacologic profile of compounds that antagonize these actions suggested that the effects of Ro 5-4864 were not mediated by "brain-type" benzodiazepine receptors. We examined a number of compounds that are structurally related to Ro 5-4864 for their capacities to displace [3H]Ro 5-4864 from "peripheral-type" binding sites and their potencies as convulsants (or as antagonists of Ro 5-4864-induced convulsions). It was observed that compounds such as KW 3600 (the N-desmethyl analog of Ro 5-4864), which have very low affinities for "peripheral-type" sites, are convulsants with a potency nearly equal to that of Ro 5-4864. In contrast, compounds such as Ro 5-6900 and PK 11195, which bind with very high affinities to "peripheral-type" binding sites, are neither convulsants nor do they antagonize the convulsant actions of Ro 5-4864. Within a series of compounds that are structurally related to Ro 5-4864 there is a good correlation (r = 0.93; p less than 0.01) between their potencies as convulsants and their capacities to displace [35S]t-butylbicyclophosphorothionate from sites that may be associated with the chloride ionophore. Thus, it appears that occupation of "peripheral-type" binding sites by high-affinity ligands may not be directly involved in the convulsant actions of Ro 5-4864 and related compounds.
Weissman
B A
BA
Cott
J
J
Jackson
J A
JA
Bolger
G T
GT
Weber
K H
KH
Horst
W D
WD
Paul
S M
SM
Skolnick
P
P
D000818:Animals; D001570:Benzodiazepinones / Q000378:metabolism / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism; D003292:Convulsants / Q000378:metabolism / Q000494:pharmacology*; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001570:Benzodiazepinones; D002712:Chlorides; D003292:Convulsants; D007473:Ion Channels; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam