Chirality of Novel Bitopic Agonists Determines Unique Pharmacology at the Dopamine D3 Receptor.

The dopamine D2/D3 receptor (DR/DR) agonists are used as therapeutics for Parkinson's disease (PD) and other motor disorders. Selective targeting of DR over DR is attractive because of DR's restricted tissue distribution with potentially fewer side-effects and its putative neuroprotective effect. However, the high sequence homology between the DR and DR poses a challenge in the development of DR selective agonists.

Positive Allosteric Modulation of the 5-HT Receptor by Indole-Based Synthetic Cannabinoids Abused by Humans.

The nonmedical (i.e., recreational) misuse of synthetic cannabinoids (SCs) is a worldwide public health problem.

Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism.

By analyzing and simulating inactive conformations of the highly homologous dopamine D and D receptors (DR and DR), we find that eticlopride binds DR in a pose very similar to that in the DR/eticlopride structure but incompatible with the DR/risperidone structure. In addition, risperidone occupies a sub-pocket near the Na binding site, whereas eticlopride does not. Based on these findings and our experimental results, we propose that the divergent receptor conformations stabilized by Na-sensitive eticlopride and Na-insensitive risperidone correspond to different degrees of inverse agonism.

Identification of Novel, Structurally Diverse, Small Molecule Modulators of GPR119.

GPR119 drug discovery efforts in the pharmaceutical industry for the treatment of type 2 diabetes mellitus (T2DM) and obesity, were initiated based on its restricted distribution in pancreas and GI tract, and its possible role in glucose homeostasis. While a number of lead series have emerged, the pharmacological endpoints they provide have not been clear. In particular, many lead series have demonstrated loss of efficacy and significant toxic side effects.