Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole

Partial agonists of the dopamine D2 receptor (D2R) have been developed to treat the symptoms of schizophrenia without causing the side effects elicited by antagonists. The receptor-ligand interactions that determine the intrinsic efficacy of such drugs, however, are poorly understood. Aripiprazole has an extended structure comprising a phenylpiperazine primary pharmacophore and a 1,2,3,4-tetrahydroquinolin-2-one secondary pharmacophore. We combined site-directed mutagenesis, analytical pharmacology, ligand fragments and molecular dynamics simulations to identify the D2R-aripiprazole interactions that contribute to affinity and efficacy. We reveal that an interaction between the secondary pharmacophore of aripiprazole and a secondary binding pocket defined by residues at the extracellular portions of transmembrane segments 1, 2 and 7 determine the intrinsic efficacy of aripiprazole. Our findings reveal a hitherto unappreciated mechanism through which to fine-tune the intrinsic efficacy of D2R agonists

Multivalent Ligands as Chemical Probes for the Investigation of Dopamine D2 Receptor Pharmacology

The dopamine D₂ receptor is a well-established therapeutic target for the treatment of central nervous system disorders such as schizophrenia and Parkinson’s disease. Although a number of treatments have been developed to target this receptor, our understanding of the structural and pharmacological aspects of the dopamine D₂ receptor are still in its infancy. This thesis describes the design, synthesis and biological evaluation of chemical probes to investigate the structure and pharmacology of the dopamine D₂ receptor. Through this work, it is envisaged that these probes will aid the development of novel treatments for central nervous system disorders with reduced side-effects

Multivalent approaches and beyond: novel tools for the investigation of dopamine D2 receptor pharmacology

The dopamine D2 receptor (D2R) has been implicated in the symptomology of disorders such as schizophrenia and Parkinson's disease. Multivalent ligands provide useful tools to investigate emerging concepts of G protein-coupled receptor drug action such as allostery, bitopic binding and receptor dimerization. This review focuses on the approaches taken toward the development of multivalent ligands for the D2R recently and highlights the challenges associated with each approach, their utility in probing D2R function and approaches to develop new D2R-targeting drugs. Furthermore, we extend our discussion to the possibility of designing multitarget ligands. The insights gained from such studies may provide the basis for improved therapeutic targeting of the D2R

The next pandemic: antimicrobial resistance

The current and continual emergence of antimicrobial-resistant bacteria remains an ‘invisible pandemic’ for now. Antimicrobial resistance (AMR) is a serious threat to global health and development and requires urgent action. The current rate of development of new antibiotics is not sufficient to prevent antimicrobial-resistant infections globally that currently kill 700,000 people each year. Antimicrobial-resistant bacterial infections are untreatable with current antibiotics. Australian research is addressing AMR, but policies supporting greater translation of research into products and solutions are required.<br/

Subtle Modifications to the Indole-2-carboxamide Motif of the Negative Allosteric Modulator N-(( trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1 H)-yl)ethyl)cyclohexyl)-1 H-indole-2-carboxamide (SB269652) Yield Dramatic Changes in Pharmacological Activity at the Dopamine D2 Receptor

SB269652 (1) is a negative allosteric modulator of the dopamine D2 receptor. Herein, we present the design, synthesis, and pharmacological evaluation of "second generation" analogues of 1 whereby subtle modifications to the indole-2-carboxamide motif confer dramatic changes in functional affinity (5000-fold increase), cooperativity (100-fold increase), and a novel action to modulate dopamine efficacy. Thus, structural changes to this region of 1 allows the generation of a novel set of analogues with distinct pharmacological properties

Subtle Modifications to the Indole-2-carboxamide Motif of the Negative Allosteric Modulator <i>N</i>‑((<i>trans</i>)‑4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1<i>H</i>)‑yl)ethyl)cyclohexyl)‑1<i>H</i>‑indole-2-carboxamide (SB269652) Yield Dramatic Changes in Pharmacological Activity at the Dopamine D₂ Receptor

SB269652 (<b>1</b>) is a negative allosteric modulator of the dopamine D₂ receptor. Herein, we present the design, synthesis, and pharmacological evaluation of “second generation” analogues of <b>1</b> whereby subtle modifications to the indole-2-carboxamide motif confer dramatic changes in functional affinity (5000-fold increase), cooperativity (100-fold increase), and a novel action to modulate dopamine efficacy. Thus, structural changes to this region of <b>1</b> allows the generation of a novel set of analogues with distinct pharmacological properties

The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions

Abstract Sodium ions (Na+) allosterically modulate the binding of orthosteric agonists and antagonists to many class A G protein-coupled receptors, including the dopamine D2 receptor (D2R). Experimental and computational evidences have revealed that this effect is mediated by the binding of Na+ to a conserved site located beneath the orthosteric binding site (OBS). SB269652 acts as a negative allosteric modulator (NAM) of the D2R that adopts an extended bitopic pose, in which the tetrahydroisoquinoline moiety interacts with the OBS and the indole-2-carboxamide moiety occupies a secondary binding pocket (SBP). In this study, we find that the presence of a Na+ within the conserved Na+-binding pocket is required for the action of SB269652. Using fragments of SB269652 and novel full-length analogues, we show that Na+ is required for the high affinity binding of the tetrahydroisoquinoline moiety within the OBS, and that the interaction of the indole-2-carboxamide moiety with the SBP determines the degree of Na+-sensitivity. Thus, we extend our understanding of the mode of action of this novel class of NAM by showing it acts synergistically with Na+ to modulate the binding of orthosteric ligands at the D2R, providing opportunities for fine-tuning of modulatory effects in future allosteric drug design efforts