Triazolodiazepines: dissociation of their Paf (platelet activating factor) antagonistic and CNS activity

1 The relationship between the activity of thieno‐ or benzo‐triazolodiazepines on platelet‐activating factor (Paf)‐induced effects and on the CNS (central nervous system) was studied in vitro and in vivo.2 Brotizolam and triazolam inhibited Paf‐induced human platelet aggregation. The IC 50 ‐ values were 0.54 and 7.6 μ m , respectively. This inhibitory effect was not blocked by the specific central‐type benzodiazepine (BDZ) antagonist, Ro 15–1788, or the specific peripheral‐type BDZ ligand, Ro 5–4846. These BDZ ligands also showed an inhibitory effect on Paf‐induced platelet aggregation (IC 50 = 200 and 560 μ m , respectively). Ro 15–1788 or Ro 5–4846 in combination with brotizolam or triazolam enhanced the Paf inhibitory effect of these triazolodiazepines. 3 In guinea‐pigs, Ro 15–1788, 100 mg kg‐1p.o. and 10 mg kg‐1 i.v. completely inhibited the hypnogenic effect of 10 mg kg −1 p.o. and 1 mg kg −1 i.v. of brotizolam, respectively. Similar results were obtained with triazolam but at higher doses. 4 In anaesthetized guinea‐pigs, a dose of 100 mg kg‐1 p.o. of Ro 15–1788 did not inhibit bronchoconstriction and hypotension caused by Paf (30 ngkg −1 min −1 i.v.). The combination of brotizolam (10 mg kg −1 p.o.) or triazolam (200 mg kg −1 p.o.) with this BDZ antagonist (100 and 400 mg kg‐1 p.o., respectively) did not affect the Paf inhibitory activity of these triazolodiazepines. 5 These results show that the Paf antagonistic properties of the triazolodiazepines can be dissociated from their CNS activity. It is conceivable that compounds of this structural type could be the forerunners of a novel series of potent Paf antagonists.