Type II β-turn mimics and polyproline II helix mimics based upon diastereoisomeric 5.6.5 spiro bicyclic scaffolds have provided two pairs of Pro-Leu-Gly-NH 2 (PLG) peptidomimetics with contrasting dopamine receptor modulating activities. Compounds 1a and 3a were found to be positive allosteric modulators of the dopamine receptor, while the corresponding diastereoisomeric compounds 1b and 3b provided the first PLG peptidomimetics with the ability to decrease the binding of agonists to the dopamine receptor. The positive allosteric modulating activity of 3a supported the hypothesis that a polyproline II helix conformation is the bioactive conformation for the PLG analogue Pro-Pro-Pro-NH 2 . The results also show that a change in the bridgehead chirality of the 5.6.5 scaffold brings about opposite effects in terms of the modulation of the dopamine receptor.

Synapsins are a family of neuron-specific phosphoproteins involved in synaptic vesicle docking, synaptogenesis, and synaptic plasticity. Previous studies have reported an increase in synapsin II protein by dopaminergic agents in the striatum, medial prefrontal cortex, and nucleus accumbens. This study investigated the mechanistic pathway involved in synapsin II regulation by dopaminergic drugs using primary midbrain neurons to determine which of several transcription factors regulates synapsin II expression. Protein kinase A (PKA) participation in the signaling pathway was examined using selective PKA inhibitors, which reduced synapsin II expression in cell cultures while dopaminergic agents were unable to increase synapsin II in the presence of the PKA inhibitor. Transcription factor involvement was further investigated using separate cultures treated with antisense deoxyoligonucleotides (ADONs) against the following transcription factors: activating protein 2 alpha (AP-2alpha), early growth response factor 1 (EGR-1), or polyoma enhancer activator-3 (PEA-3). Selective knockdown of AP-2alpha by ADONs reduced synapsin II levels, whereas treatment with EGR-1 and PEA-3 ADONs did not affect synapsin II expression. Furthermore, dopaminergic agents were no longer able to influence synapsin II concentrations following AP-2alpha knockdown. Collectively, these results indicate that a cyclic adenosine-3',5'-monophosphate/PKA-dependent mechanism involving the AP-2alpha transcription factor is likely responsible for the increase in neuronal synapsin II following dopamine D1 receptor stimulation or dopamine D2 receptor inhibition.