Syntheses of 5-thienyl- and 5-furyl-substituted benzodiazepines: Probes of the pharmacophore for benzodiazepine receptor agonists

Article abstract of DOI:10.1016/0223-5234(96)88259-6

The synthesis of 5-thienyl- and 5-furyl-substituted benzodiazepines is described. These compounds were employed to probe the lipophilic pocket (L₃) of the benzodiazepine receptor (BzR) and to determine the effect of occupation of L₃ on biological activity. Of the new analogs synthesized, the 5-(2-thienyl)-benzodiazepines 6a and 7a displayed high affinity for the BzR (IC₅₀ 28 and 18 nM, respectively) and exhibited both anticonvulsant (ED₅₀ ~ 9 and 3 mg/kg) and muscle relaxant (ED₅₀ ~ 10 and 7 mg/kg) activity. The 5-(3-thienyl)benzodiazepines 6d and 7d displayed only moderate affinity for the BzR (IC₅₀ 140 and 110 nM) and exhibited no biological activity (no anticonvulsant or muscle relaxant activity) at doses up to 40 mg/kg. The 5-(2-furyl)benzodiazepines (6b, 7b, 19b and 20b) exhibit low affinities for the BzR. These in vitro and in vivo findings are consistent with our model suggesting that pocket L₃ is very sensitive to lipophilic effects. Thus, decreasing the lipophilicity of functional groups which occupy this region decreases ligand affinity at BzR. The 2'-halogen (F or Cl) substituent of the 5-phenylbenzodiazepines increases ligand affinity in vitro because the active conformation of the phenyl N(4)=C(5)-C(1')=C(2') moiety is syn rather than anti. The syn conformation permits the 2'-halogen (F or Cl) atom to interact at the hydrogen bonding site H₂ and form a stable three-centered hydrogen bond in the proposed ligand binding cleft. The 3-thienyl and 2-furyl groups decrease the lipophilicity of the substituent which occupies L₃ but do not form a hydrogen bond at H₂, thus resulting in a diminished affinity at BzR.