Recent advances in the search for D3- and D4-selective drugs: probes, models and candidates

Structure–Activity Study of N-((trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a Bitopic Ligand That Acts as a Negative Allosteric Modulator of the Dopamine D2 Receptor

“…14 Such appendages have been proposed to extend into a secondary pocket away from the orthosteric pocket. 14,18,19 We have recently confirmed that 1 displays limited negative allosteric cooperativity at the D 2 R with a sub-micromolar binding affinity, but found that truncated derivatives of 1 containing a THIQ moiety act in a competitive manner with dopamine.…”

“…14 Such appendages have been proposed to extend into a secondary pocket away from the orthosteric pocket. 14,18,19 We have recently confirmed that 1 displays limited negative allosteric cooperativity at the D 2 R with a sub-micromolar binding affinity, but found that truncated derivatives of 1 containing a THIQ moiety act in a competitive manner with dopamine. 20 We demonstrated that 1 acts via a novel mechanism, engaging one protomer of a D 2 R dimer in a dual orthosteric/allosteric (or bitopic) mode, to negatively modulate dopamine binding and function at the other protomer (Figure 1).…”

Dopamine D3 receptor agonists as pharmacological tools

“…PLD dysregulation by α-synuclein may cause neuronal cell loss leading to Parkinson's disease (Peng and Frohman, 2012). Nevertheless understanding of the physiological signaling pathways of D 3 receptor is still challenging by clarification of main signaling pathway (Levant, 1997;Löber et al, 2011).…”

“…The key steps in signal transduction from G-protein activation over second and third signaling of the D 3 receptor subtype are summarized in the following (for further reviews see: Ahlgren-Beckendorf and Levant, 2004;Löber et al, 2011). Excellent detailed descriptions of dopamine receptor signaling including all subtypes are given by Missale et al (1998), Neve et al (2004) or Beaulieu and Gainetdinov (2011).…”

Genetic Pharmacotherapy

“…The prediction was that D3 selective antagonists would prove therapeutic with reduced motor side effects. Although a recently revealed amino acid difference between the highly homologous D2 and D3 receptors will provide new guidance for the design of new D3 receptor-selective ligands together with resolution of the crystal structure (Chien et al, 2010), sufficiently selective ligands are still not available (Lã Ber et al, 2011). Because of the catch-22 that therapeutic efficacy of drug targeting cannot be tested until selective ligands are available, and because the past two decades have yet to yield a sufficiently selective ligand, the proof-of-concept study to demonstrate the therapeutic potential of selective D3 inhibition has yet to be done.…”