A 1,4-benzodiazepine analogue alprazolam (1) undergoes ring-opening hydrolysis under acidic conditions to form a triazolobenzophenone (2). At a neutral pH, 2 rapidly and quantitatively cyclizes back to 1. This facile reversible reaction was utilized in developing water-soluble prodrugs of 1 in which the "solubility anchoring" acyl moieties are formyl, acetyl, succinyl, glycyl, leucyl, and gamma-aminobutyryl groups. These compounds were prepared directly from 2 and corresponding acids through DCC coupling in a 1:1 mixture of H2O and THF. They should be stable in aqueous media at room temperature. Promoieties used should be nontoxic at an intended dose level. In vitro human serum hydrolysis study showed that only glycyl and leucyl amides were able to regenerate 1 within a reasonable period of time. Ex vivo competitive receptor binding assay in mice with [3H]flunitrazepam indicated that leucyl amide prodrug should be able to produce a rapid onset of the intrinsic central nervous system activity of 1 when parenterally administered. For all compounds studied, the final outcome of the biological response appears to be kinetically controlled, rather than by an unfavorable equilibrium, particularly by the first step in which the amide bond is hydrolyzed in vivo.