Dopamine D₄ Receptor-Selective Compounds Reveal Structure–Activity Relationships that Engender Agonist Efficacy

Abstract

The dopamine D4 receptor (D4R) plays important roles in cognition, attention, and decision making. Novel D4R-selective ligands have promise in medication development for neuropsychiatric conditions, including Alzheimer’s disease and substance use disorders. To identify new D4R-selective ligands, and to understand the molecular determinants of agonist efficacy at D4R, we report a series of eighteen novel ligands based on the classical D4R agonist A-412997 (1, 2-(4-(pyridin-2-yl)piperidin-1-yl)-N-(m-tolyl)acetamide). Compounds were profiled using radioligand binding displacement assays, β-arrestin recruitment assays, cyclic AMP inhibition assays, and molecular dynamics computational modeling. We identified several novel D4R-selective (Ki ≤ 4.3 nM and >100-fold vs other D2-like receptors) compounds with diverse partial agonist and antagonist profiles, falling into three structural groups. These compounds highlight receptor–ligand interactions that control efficacy at D2-like receptors and may provide insights into targeted drug discovery, leading to a better understanding of the role of D4Rs in neuropsychiatric disorders.

Chiral Cyclic Aliphatic Linkers as Building Blocks for Selective Dopamine D2 or D3 Receptor Agonists

“…To generate SAR, the new library of compounds was tested in radioligand binding assays at both human-cloned D 2 R (hD 2 R) and D 3 R (hD 3 R) receptor subtypes using agonist [ 3 H]-( R )-(+)-7-OH-DPAT and/or antagonist [ 3 H]- N -methylspiperone (Table ). We have found that the D 2 R active state agonist binding is significantly more sensitive ,,, to the radioligand used with respect to D 3 R. As a consequence, the use of [ 3 H]-( R )-(+)-7-OH-DPAT allows an accurate determination of apparent affinities for both targets, and selectivity, valuable to better correlate measured binding values with predicted and/or experimentally determined functional profiles, ,,, which would be otherwise dramatically overestimated in favor of the D 3 R when the antagonist [ 3 H]- N -methylspiperone is used [Table , comparison between D 3 R and D 2 R selectivity ratios between K i s obtained using [ 3 H]- N -methylspiperone or [ 3 H]-( R )-(+)-7-OH-DPAT].…”

Exception That Proves the Rule: Investigation of Privileged Stereochemistry in Designing Dopamine D3R Bitopic Agonists

“…All new compounds were tested for their affinities at hD 2 R and hD 3 R, in competition with the agonist [ 3 H]-( R )-(+)-7-OH-DPAT (Table ). As previously discussed, ,, the ability to evaluate agonist affinities for the receptors of interest in their active states allows for a better estimation of subtype selectivity and better resembles the ligand–receptor interaction under physiological conditions where only a fraction of the total available receptors are in the active state, and the agonists have to compete with endogenous dopamine (DA) for the OBS. Moreover, the radiolabeled agonist simplifies the binding protocol for testing new agonists’ affinity in cell membrane preparations and generates monophasic curves, with optimal fitting, representing the high-affinity agonist bound state (Figure S6).…”

“…Advances in X-ray crystallography and cryomicroscopy have enabled the resolution of several GPCR structures in their active and inactive states, empowering a target-driven drug design approach . Crystal structures of D 2 R, D 3 R, and D 4 R have highlighted the existence of extended and structurally less conserved secondary binding pockets (SBPs). − Targeting this SBP, which often can function as an allosteric binding site (ABS), whose engagement can positively (positive allosteric modulator, PAM) or negatively (negative allosteric modulator, NAM) modulate the OBS functional response, has emerged as an attractive approach to selectively target GPCRs with small molecules to control specific pharmacological behaviors. Several academic research laboratories have pioneered the development of allosteric modulators selectively targeting GPCR subtypes. − …”

Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders

“…D 4 R, mainly expressed in the hippocampus and prefrontal cortex, affects exploratory behavior, attention, and inhibitory avoidance tasks. Activation of D 4 R is useful for treating cognitive deficits associated with schizophrenia and attention-deficit/hyperactivity disorders [8]. On the other hand, D 1 -like D 1 R, which stimulates G a s/olf to enhance adenylate cyclase activity and cAMP production, is the most abundant dopamine receptor in the forebrain [6].…”