Development of pyrimidone D1 dopamine receptor positive allosteric modulators.

MLS1082 is a structurally novel pyrimidone-based D1-like dopamine receptor positive allosteric modulator. Potentiation of D1 dopamine receptor (D1R) signaling is a therapeutic strategy for treating neurocognitive disorders. Here, we investigate the relationship between D1R potentiation and two prominent structural features of MLS1082, namely the pendant N-aryl and C-alkyl groups on the pyrimidone ring.

A Mechanism Linking Two Known Vulnerability Factors for Alcohol Abuse: Heightened Alcohol Stimulation and Low Striatal Dopamine D2 Receptors.

Alcohol produces both stimulant and sedative effects in humans and rodents. In humans, alcohol abuse disorder is associated with a higher stimulant and lower sedative responses to alcohol. Here, we show that this association is conserved in mice and demonstrate a causal link with another liability factor: low expression of striatal dopamine D2 receptors (D2Rs).

Identification of Positive Allosteric Modulators of the D Dopamine Receptor That Act at Diverse Binding Sites.

The D dopamine receptor is linked to a variety of neuropsychiatric disorders and represents an attractive drug target for the enhancement of cognition in schizophrenia, Alzheimer disease, and other disorders. Positive allosteric modulators (PAMs), with their potential for greater selectivity and larger therapeutic windows, may represent a viable drug development strategy, as orthosteric D receptor agonists possess known clinical liabilities. We discovered two structurally distinct D receptor PAMs, MLS6585 and MLS1082, via a high-throughput screen of the NIH Molecular Libraries program small-molecule library.

Protein kinase C beta regulates the D₂-like dopamine autoreceptor.

The focus of this study was the regulation of the D2-like dopamine autoreceptor (D2 autoreceptor) by protein kinase Cβ, a member of the protein kinase C (PKC) family. Together with the dopamine transporter, the D2 autoreceptor regulates the level of extracellular dopamine and thus dopaminergic signaling. PKC regulates neuronal signaling via several mechanisms, including desensitizing autoreceptors to increase the release of several different neurotransmitters.

An N-terminal threonine mutation produces an efflux-favorable, sodium-primed conformation of the human dopamine transporter.

The dopamine transporter (DAT) reversibly transports dopamine (DA) through a series of conformational transitions. Alanine (T62A) or aspartate (T62D) mutagenesis of Thr62 revealed T62D-human (h)DAT partitions in a predominately efflux-preferring conformation. Compared with wild-type (WT), T62D-hDAT exhibits reduced [(3)H]DA uptake and enhanced baseline DA efflux, whereas T62A-hDAT and WT-hDAT function in an influx-preferring conformation.

Leptin promotes dopamine transporter and tyrosine hydroxylase activity in the nucleus accumbens of Sprague-Dawley rats.

Adipocytes produce the hormone, leptin, in proportion to fat mass to signal the status of body energy stores to the central nervous system, thereby modulating food intake and energy homeostasis. In addition to controlling satiety, leptin suppresses the reward value of food, which is controlled by the mesolimbic dopamine (DA) system. Previous results from leptin-deficient ob/ob animals suggest that chronic leptin deficiency decreases DA content in the mesolimbic DA system, thereby decreasing the response to amphetamine (AMPH).