Design, Synthesis, and Evaluation of Functionalized 5-(4-arylpiperazin-1-yl)-N-Quinolinyl-pentanamides as Selective Dopamine D3 Receptor Ligands

Dopamine (1) plays a key role in normal physiological pathways in both the central nervous system and the periphery. The physiological impact of this neurotransmitter is mediated through its interaction with family of G-protein-coupled receptors (GPCRs). These receptors are designated as D1, D2, D3, D4, and D5 and divided into two sub-families, the D1-like sub-family (D1 and D5) and D2-like sub-family (D2, D3 and D4) based on pharmacological properties, amino acid homology, and genetic organization. Aberrant D3 activity has been linked to multiple diseases and conditions such as depression, schizophrenia, substance use disorder, inflammatory diseases, and Parkinson’s disease (PD). As part of our on-going program focused on the identification of novel D3 ligands, we have identified a novel series of 5-(4-arylpiperazin-1-yl)-N-quinolinyl-pentanamides that are high affinity ligands for this receptor.

Design, Synthesis, And Evaluation of Functionalized Diamino-butylbenzamides As Selective Dopamine D3 Receptor Ligands

Substance use disorder remains a major, unmet medical need. Cocaine is one of the most commonly abused recreational drugs and in 2018, there were over 5.5 million current cocaine users. There are no approved therapies for the treatment of cocaine use disorder, but the D3 dopamine receptor has been identified as a potential therapeutic target. We have identified a series of functionalized diamino-butylbenzamides that are potent D3 binders with moderate to high selectivity for D3 over D2.

Zebrafish Larvae's Response to Electricity is Mediated by Dopaminergic Agonists and Antagonists

The signaling molecular mechanisms in zebrafish response to electricity are unknown, so here we asked if changes to dopaminergic signaling pathways can affect their electrically-evoked locomotion. To answer this question, the effects of multiple selective and non-selective dopamine compounds on the electric response of zebrafish larvae is investigated. A microfluidic device with enhanced control of experimentation with multiple larvae is used, which features a novel design to immobilize four zebrafish larvae in parallel and expose them to electric current that induces tail locomotion. In 6 days post-fertilization zebrafish larvae, the electric induced locomotor response is quantified in terms of the tail movement duration and beating frequency to discern the effect of non-lethal concentrations of dopaminergic agonists (apomorphine, SKF-81297, and quinpirole), and antagonists (butaclamol, SCH-23390, and haloperidol). All dopamine antagonists decrease locomotor activity, while dopamine agonists do not induce similar behaviours in larvae. The D2- like selective dopamine agonist quinpirole enhances movement. However, exposure to non-selective and D1-selective dopamine agonists apomorphine and SKF-81297 cause no significant change in the electric response. Exposing larvae that were pre-treated with butaclamol and haloperidol to apomorphine and quinpirole, respectively, restores electric locomotion. The results demonstrate a correlation between electric response and the dopamine signalling pathway. We propose that the electrofluidic assay has profound application potential as a chemical screening method when investigating biological pathways, behaviors, and brain disorders.

An attempt at the hydrated imidazoline ring expansion (HIRE) of diarene-fused [1,4]diazepinones delivers selective dopamine D2 receptor ligands

Attempts to extend the hydrated imidazoline ring expansion (HIRE) strategy to a series of diarene-fused [1,4]diazepinones (earlier applied successfully to bis-pyrido substrate nevirapine) resulted in no ring expansion but rather 2-aminoethyl side chain expulsion. This seeming setback (setting the limitations to the HIRE methodology substrate scope) led to the discovery of selective dopamine D2 ligands with elements of structure-activity relationships.