RP-59037 AND RP-60503 - ANXIOLYTIC CYCLOPYRROLONE DERIVATIVES WITH LOW SEDATIVE POTENTIAL - INTERACTION WITH THE GAMMA-AMINOBUTYRIC-ACID (A) BENZODIAZEPINE RECEPTOR COMPLEX AND BEHAVIORAL-EFFECTS IN THE RODENT

This study describes the pharmacological properties of two novel cyclo pyrrolone derivatives, RP 59037 n-1,8-yl)-3-(5-methyl-2-oxohexyl)isoin dolin-1-one] and RP 60503 ridin-1,8-yl)isoindolin-1-yl-4-acetamidobuty rate], in the rodent. These compounds possess high affinity for the be nzodiazepine binding site on the gamma-aminobutyric acidA receptor in rat cerebrocortical membranes with K(i) values of 0.98 nM (RP 59037) a nd 1.16 nM (RP 60503). Neither compound discriminates between the puta tive benzodiazepine BZ1 and BZ2 binding site subtypes present in the r at cerebellum and hippocampus, respectively. Both compounds protect mi ce against pentylenetetrazole-induced seizures with ID50 values of 0.2 1 mg . kg-1 p.o. (RP 59037) and 5.96 mg . kg-1 p.o. (RP 60503). The tw o compounds displayed a restricted anticonvulsant profile compared to diazepam and, in this respect, resembled the pyrazoloquinoline partial agonist, CGS 9896. RP 59037 and RP 60503 were active in two rat model s predictive of anxiolytic drug action, a modified Geller-Seifter conf lict paradigm (minimal effective dose, 0.33 mg . kg-1 p.o. for RP 5903 7 and 5 mg . kg-1 p.o. for RP 60503) and the elevated plus maze (minim al effective dose, 0.33 mg . kg-1 p.o. for RP 59037 and 5 mg 1 kg-1 p. o. for RP 60503). Only very low activities were observed in tests of s edative or myorelaxant effects (ED50 > 50 mg . kg-1 p.o.). It is concl uded that the two cyclopyrrolones possess a dissociated behavioral pro file, displaying potent anxiolytic and anticonvulsant properties with little or no sedative or myorelaxant effects. Although both compounds appear to be partial agonists at their allosteric recognition site on the gamma-aminobutyric acid(A) receptor, RP 60503 seems to be more dis sociated than RP 59037, which would be compatible with it having lower intrinsic activity. This difference is reflected in a higher receptor occupancy requirement for activity, and a smaller modulatory effect o n the binding of t-[S-35]butylbicyclophosphothionate.