Association and agonistic action of DN-2327, a novel isoindoline derivative, GABAB receptor in brain.

The association and action of DN-2327, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-[(1,4-dioxa-8- azaspiro[4,5]dec-8-yl)carbonylmethyl]isoindolin-1-one, on the gamma-aminobutyric acid (GABA)B receptor in rat brain have been examined. DN-2327 inhibited the binding of [3H]GABA to GABAB receptor in crude synaptic membrane obtained from rat brain. The Scatchard analysis of [3H]GABA binding to GABAB receptor indicated that DN-2327 induced the decrease in affinity of both high and low affinity binding sites without changing the Bmax values. The forskolin-stimulated adenylate cyclase activity in slices from rat cerebral cortex was significantly suppressed by the addition of DN-2327. Furthermore, this inhibition by DN-2327 was eliminated by the simultaneous additions of 2-hydroxy saclofen or CGP 55845A, GABAB receptor antagonists. These results suggest that DN-2327 may have not only a high association with GABAB receptor but also an agonistic action on the receptor.