Brain receptor binding and lipophilic character of benzodiazepines.

A series of measurements of the potency of 26 benzodiazepines (BDZs) to inhibit the binding of [3H]diazepam to rat brain synaptosomal membranes has been undertaken. All compounds studied are NO2 or Cl 7-substituted, a class of BDZs known to have the highest biological activities and binding affinities (expressed as Ki). The results show that: (a) 2'-unsubstituted BDZs display a parabolic dependence of -log Ki values on lipophilic character of the molecule (expressed by means of the chromatographic Rm value); (b) 2'-halogen substituted BDZs show quite high binding affinities (ki values in the range 2-5 nM) giving rise to another class of BDZs whose dependence on the lipophilic character remains to be studied; and (c) BDZs lacking the carbonyl oxygen at position 2 (see Table 1), and having an oxygen at position 4, show low or very low binding affinities (Ki values in the range 600-7000 nM). Moreover for the compounds under examination, statistically significant correlations have been obtained between -log Ki values and psychopharmacological activity data.