BIDIRECTIONAL EFFICACY AT BENZODIAZEPINE RECEPTORS OF A SERIES OF IMIDAZOPYRIMIDINES ILLUSTRATED IN DRUG DISCRIMINATION STUDIES

Male Lister rats were trained to discriminate either chlordiazepoxide (CDZP), the benzodiazepine (BDZ) receptor partial agonist RU32698, or leptazol from vehicle on a fixed ratio 20 schedule. From 10 imidazopyrimidine BDZ receptor ligands tested four showed the profiles of agonists in that they substituted for CDZP and RU32698 and antagonized the leptazol cue. RU33203 depressed rates of responding in tests with all three cues, RU32698 only depressed responding at the highest dose in tests in the leptazol cue, and RU33543 or RU32514 did not alter rates of responding. Antagonism of the leptazol cue by RU32514 showed a 50% maximum. These data suggest that the agonist efficacies of these compounds rank RU33203 > RU32698 > RU33543 > RU32514. The other six compounds showed inverse agonist profiles as they antagonized the CDZP cue and substituted for leptazol. Three compounds tested also antagonized the RU32698 cue. RU34113 was equipotent in antagonizing the CDZP cue and substituting for leptazol. RU33094 and RU34134 were clearly more potent in antagonizing the CDZP cue while RU33697, RU33356, and RU34000 showed intermediate profiles. All six compounds decreased rates of responding at doses that maximally antagonized the CDZP cue. These data suggest that RU34113 has the strongest inverse agonist efficacy and RU33094 and RU34134 the weakest efficacy. Structure-efficacy relationships within this series of imidazopyrimidines are discussed.