Analogs of the previously reported antimalarial hybrid compounds 8b and 12 were proposed with the aim of identifying compounds with improved solubility and retained antimalarial potency. In silico characterization predicted improved solubilities of the analogs, particularly at low pH; they retained acceptable predicted permeability properties, but were predicted to be susceptible to hepatic metabolism. These analogs were synthesized and found to exhibit notable in vitro antimalarial activity. Compounds 25 and 27 were the most active of the analogs. In vitro metabolism studies indicated susceptibility of the analogs to hepatic metabolism. There was also evidence of primary glucuronidation for analogs 24 – 27. Presumed cis - trans isomerism of 12, 22 and 23 under in vitro metabolism assay conditions was also observed, with differences in the nature and rates of metabolism observed between isomers. Biochemical studies strongly suggested that inhibition of hemozoin formation is the primary mechanism of action of these analogs.

SB269652 is a negative allosteric modulator of the dopamine D receptor (DR) yet possesses structural similarity to ligands with a competitive mode of interaction. In this study, we aimed to understand the ligand-receptor interactions that confer its allosteric action. We combined site-directed mutagenesis with molecular dynamics simulations using both SB269652 and derivatives from our previous structure activity studies. We identify residues within the conserved orthosteric binding site (OBS) and a secondary binding pocket (SBP) that determine affinity and cooperativity. Our results indicate that interaction with the SBP is a requirement for allosteric pharmacology, but that both competitive and allosteric derivatives of SB269652 can display sensitivity to the mutation of a glutamate residue (E95) within the SBP. Our findings provide the molecular basis for the differences in affinity between SB269652 derivatives, and reveal how changes to interactions made by the primary pharmacophore of SB269652 in the orthosteric pocket can confer changes in the interactions made by the secondary pharmacophore in the SBP. Our insights provide a structure-activity framework towards rational optimization of bitopic ligands for DR with tailored competitive versus allosteric properties.

SB269652 (1) is a negative allosteric modulator of the dopamine D 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.

Partial agonists of the dopamine D 2 receptor 18 (D 2 R) 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 *

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.