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.
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001923:Brain Chemistry; D003975:Diazepam / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D011963:Receptors, GABA-A; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000378:metabolism*
D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D003975:Diazepam