Pro‐ and anti‐convulsant properties of PK 11195, a ligand for benzodiazepine binding sites: development of tolerance

1 Ro 5–4864 is a benzodiazepine that differs from diazepam only in a p ‐chloro substituent and yet is inactive at the classical CNS binding sites. However it is a potent ligand for the peripheral type of benzodiazepine binding sites. PK 11195 is an isoquinoline carboxamide derivative that potently displaces [ 3 H]‐Ro 5–4864 from its binding sites. 2 PK 11195 (30–60 mg kg −1 ) significantly reduced the incidence of convulsions caused by Ro 5–4864 (30 mg kg −1 ). PK 11195 (up to 120 mg kg −1 ) was ineffective at counteracting seizures caused by the convulsant benzodiazepine Ro 5–3663, although this dose did increase the latency to seize after injection with pentylenetetrazole. PK 11195 had no anticonvulsant actions against picrotoxin, and at 60 mg kg −1 reduced the latency to seize. This possible proconvulsant property of the isoquinoline was further explored. 3 PK 11195 (30–90 mg kg −1 ) had proconvulsant actions when combined with subconvulsant doses of strychnine and picrotoxin, but had none when combined with pentylenetetrazole. 4 No significant tolerance developed to the anticonvulsant action of PK 11195 (30 mg kg −1 ) even after 25 days of dosing daily. In contrast, there was rapid tolerance (within 5 days) to the proconvulsant action of PK 11195 (60 mg kg −1 ) with picrotoxin (3 mg kg −1 ). 5 There was no cross‐tolerance between the anticonvulsant actions of diazepam and PK 11195, which suggests that these two drugs act at different sites, as would be predicted from the results of the binding studies. 6 The possible sites of action and clinical relevance of these effects are discussed.