Brain receptor binding and lipophilic character of benzodiazepines

Abstract

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 NO 2 or Cl 7-substituted, a class of BDZs known to have the highest biological activities and binding affinities (expressed as K i ). The results show that: (a) 2′-unsubstituted BDZs display a parabolic dependence of —log K i values on lipophilic character of the molecule (expressed by means of the chromatographic R m value); (b) 2′-halogen substituted BDZs show quite high binding affinities ( k i 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 ( K i values in the range 600–7000 nM). Moreover for the compounds under examination, statistically significant correlations have been obtained between -log K i values and psychopharmacological activity data.