In Vitro Characterization Of Slv308 (7-[4-Methyl-1-Piperazinyl]-2(3h)-Benzoxazolone, Monohydrochloride): A Novel Partial Dopamine D-2 And D-3 Receptor Agonist And Serotonin 5-Ht1a Receptor Agonist

Present Parkinson's disease treatment strategies are far from ideal for a variety of reasons; it has therefore been suggested that partial dopamine receptor agonism might be a potential therapeutic approach with potentially fewer side effects. In the present study, we describe the in vitro characterization of the nonergot ligand SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolonemonohydrochloride). SLV308 binds to dopamine D-2, D-3, and D-4 receptors and 5-HT1A receptors and is a partial agonist at dopamine D-2 and D-3 receptors and a full agonist at serotonin 5-HT1A receptors. At cloned human dopamine D-2, L receptors, SLV308 acted as a potent but partial D-2 receptor agonist (pEC(50) = 8.0 and pA(2) = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D-3 receptors, SLV308 acted as a partial agonist in the induction of [S-35]GTP gamma S binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [S-35]GTR gamma S binding (pA(2) = 9-0). SLV308 acted as a full 5-HT1A receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT1A receptors but with low potency (pEC(50) = 6.3). In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D-2 and D-3 receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K+-stimulated [3 HI-dopamine release from rat striatal slices (pA(2) = 8.5). In the same paradigm, SLV308 had antagonist properties in the presence of quinpirole (pA2 = 8.5), but the partial D-2 agonist terguride had much stronger antagonistic properties. In conclusion, SLV308 combines high potency partial agonism at dopamine D-2 and D-3 receptors with full efficacy low potency serotonin 5-HT1A receptor agonism and is worthy of profiling in in vivo models of Parkinson's disease.