A series of new aporphine analogues were synthesized and pharmacologically evaluated. 11-Allyloxy-(17), 11-propargyloxy-(20), and dihydrofuro-(19) aporphines displayed the highest affinity at the 5-HT(1A) receptor with K(i) values of 12.0, 14.0, and 6.7 nM, respectively. The high binding potential of the diastereomeric mixture of aporphine 19 was found residing in the cis-diastereomer (cis-19). [(35)S]GTP gamma S function assays on 5-HT(1A) receptor indicated that aporphines 17 and 20 were partial agonists, while trans-19 behaved as a high efficacy full antagonist and cis-19 was a full agonist. The agonistic property of cis-19 at the 5-HT(1A) receptor was further confirmed in vitro and in vivo. This compound may be useful as a potential treatment for anxiety.

3‐methyl‐6‐chloro‐7,8‐hydroxy‐1‐(3‐methylphenyl)‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine (SKF83959), a selective agonist for the putative phosphatidylinositol (PI)‐linked dopamine receptor (DAR), has been shown to possess potent anti‐Parkinson disease effects but produces less dyskinesia and motor fluctuation that are frequently observed in Parkinson disease drug therapies. The present study was designed to detect the neuroprotection of SKF83959 and its potential mechanism for the effect in cultured rat cortical cells. The presence of SKF83959 with a dose range of 0.1–30 μmol/L improved H2O2‐reduced cell viability in a dose‐dependent manner. The anti‐apoptotic action of SKF83959 was partially abolished by pre‐application of the D1 antagonist SCH23390 (30 μmol/L) and the PI 3‐kinase (PI 3‐K) inhibitor LY294002 but not by the MEK1/2 inhibitor PD98059 (30 μmol/L). Moreover, SKF83959 treatment significantly inhibited H2O2‐activated glycogen synthase kinase‐3β (GSK‐3β) which was associated with the drug’s neuroprotective effect, but this inhibition was attenuated by SCH23390 and a selective PI 3‐K inhibitor. Moreover, the application of either SKF83959 or a pharmacological inhibitor of GSK‐3β attenuated the inhibition by H2O2 on the expression of inducible NO synthase and production of NO. This indicates that D1‐like receptor, presumably PI‐linked D1 receptor, ‐mediated alteration of PI 3‐K/Akt/GSK‐3β pathway is involved in the neuroprotection by SKF83959. In addition, SKF83959 also effectively decreased the level of the lipid peroxidation and increased the activity of GSH‐peroxidase altered by H2O2. These results suggest that SKF83959 exerts its neuroprotective effect through both receptor‐dependent and independent mechanisms: Inhibition of GSK‐3β and consequently increasing the expression of inducible NO synthase via putative PI‐linked DAR; and its anti‐oxidative activity which is independent of DAR.

The present study aims to define the role of postsynaptic density (PSD)-95 in the regulation of dopamine (DA) receptor function. We found that PSD-95 physically associates with either D1 or D2 DA receptors in co-transfected HEK-293 cells. Stimulation of DA receptors altered the association between D1 receptor and PSD-95 in a time-dependent manner. Functional assays indicated that PSD-95 co-expression did not affect D1 receptor-stimulated cAMP production, Gs-protein activation or receptor desensitization. However, PSD-95 accelerated the recovery of internalized membrane receptors by promoting receptor recycling, thus resulting in enhanced resensitization of internalized D1 receptors. Our results provide a novel mechanism for regulating DA receptor recycling that may play an important role in postsynaptic DA functional modulation and synaptic neuroplasticity.