“Peripheral‐Type”Binding Sites for Benzodiazepines in Brain: Relationship to the Convulsant Actions of Ro 5–4864

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Abstract
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 < 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.