RP 59037 and RP 60503: anxiolytic cyclopyrrolone derivatives with low sedative potential. interaction with the gamma-aminobutyric acidA/benzodiazepine receptor complex and behavioral effects in the rodent.
1993
This study describes the pharmacological properties of two novel
cyclopyrrolonederivatives, RP 59037 [2-(7-chloro-2-naphthyridin-1,8-yl)-3-(5- methyl-2-oxohexyl)
isoindolin-1-one] and RP 60503 [2-(7-chloro-2-naphthyridin-1,8-yl)
isoindolin-1-yl-4- acetamidobutyrate], in the rodent. These compounds possess high affinity for the benzodiazepine binding site on the gamma-
aminobutyricacidA receptor in rat cerebrocortical membranes with Ki values of 0.98 nM (RP 59037) and 1.16 nM (RP 60503). Neither compound discriminates between the putative benzodiazepine BZ1 and BZ2 binding site subtypes present in the rat cerebellum and hippocampus, respectively. Both compounds protect mice against
pentylenetetrazole-induced seizures with ID50 values of 0.21 mg.kg-1 p.o. (RP 59037) and 5.96 mg.kg-1 p.o. (RP 60503). The two 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 models predictive of
anxiolytic
drug action, a modified Geller-Seifter conflict paradigm (minimal effective dose, 0.33 mg.kg-1 p.o. for RP 59037 and 5 mg.kg-1 p.o. for RP 60503) and the
elevated plus maze(minimal effective dose, 0.33 mg.kg-1 p.o. for RP 59037 and 5 mg.kg-1 p.o. for RP 60503). Only very low activities were observed in tests of sedative or myorelaxant effects (
ED50> 50 mg.kg-1 p.o.). It is concluded that the two
cyclopyrrolonespossess a dissociated behavioral profile, displaying potent
anxiolyticand anticonvulsant properties with little or no sedative or myorelaxant effects. Although both compounds appear to be
partial agonistsat their allosteric recognition site on the gamma-
aminobutyricacidA receptor, RP 60503 seems to be more dissociated 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 on the binding of t-[35S]butylbicyclophosphothionate.
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