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

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Dopamine D2-like receptors (including D2, D3 and D4) belong to the ‘rhodopsin-like’ family of G protein-coupled receptors (GPCRs), which represent the largest group of targets for bioactive molecules. Due to their high sequence similarity, the design of subtype-selective ligands requires rational and effective strategies. The general formula of 1,4-disubstituted aromatic piperidines and piperazines (1,4-DAPs) was extracted from classical dopaminergic drugs. The biological properties of this compound family are encoded by an aromatic head group that controls intrinsic activity, an amine moiety and a lipophilic appendage. D3- and D4-selective molecular probes and drug candidates were generated from the general formula of 1,4-DAP. Formal structural rearrangement led to investigational drugs beyond the 1,4-DAP structure. The very recent publication of the X-ray crystal structure of D3 should facilitate efficient discovery of unprecedented chemotypes. However, the development of D3-selective agonists, functionally selective ligands and the exploitation of homo- and heteromers remain challenging.

Introduction

Parallel to gaining a more detailed insight into subtype-specific receptor pharmacology and to the evaluation of respective treatment opportunities, the available dopaminergic ligands have undergone a structural evolution. Thus, a rational and efficient strategy has become necessary to develop subtype-selective ligands. This challenge is predominantly based on a distinct structural homology among the D2-like receptors. For example, the sequence similarities for the predicted transmembrane (TM) regions are 72% for D2/D4, 73% for D3/D4, and 90% for D2 versus D3 receptors [1]. According to homology modelling studies based on the crystal structure of the β2 adrenoreceptor [2], the binding pockets also show high similarity: 19 of 21 residues contacting the binding site crevice are identical between D2 and D3. Thus, it becomes obvious that the improvement in selectivity is a challenging task, and that recent success is hardly explainable on a structural molecular level. As a complement to previous reviews 3, 4, 5, 6, we will focus on the very recent developments of D3-and D4-selective tools and drug candidates.

Section snippets

Dopaminergic drugs are not subtype-selective

Dopamine receptors belong to the ‘rhodopsin-like’ family of GPCRs, which represent the largest group of targets for bioactive molecules and which are involved in >25% of marketed drugs [7]. The neurotransmitter dopamine mediates its physiological effects through interaction with two receptor subfamilies: the Gs-coupled D1-like (including D1 and D5) and the Gi/o-coupled D2-like receptors (including D2, D3 and D4) [8]. Interestingly, none of the dopaminergic drugs on the market can be considered

The D3 receptor as a drug target

D3 receptors have the highest density in the ventral striatum (islands of Calleja) and in the nucleus accumbens (Table 1). Expression levels of the D3 receptor are approximately tenfold lower compared with the D2 subtype. It appears that a portion of D3 is localized presynaptically and functions as an autoreceptor to modulate neuronal firing, as well as the synthesis and release of dopamine (Table 1). Since the D3 receptor was cloned in 1990 [13], various efforts have been dedicated to the

The dopamine D4 receptor as a drug target

The dopamine D4 receptor can be found in the cerebral cortex, amygdala, hippocampus and striatum but at a much lower density compared with other dopamine receptor subtypes (Table 1) [25]. D4 is mainly localized to GABAergic neurons and inhibits glutamatergic activity in the prefrontal cortex, where activation of the D4 receptor reduces the signaling effects of N-methyl D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) [26]. The role of the D4 receptor as a drug

D3/D4 in the periphery

An increasing body of evidence demonstrates that dopamine plays an important part in the periphery. The abnormal expression or function of dopamine receptors on T cells is associated with altered immune function in patients with multiple sclerosis, schizophrenia, PD, and Alzheimer's disease [34]. Often, the changes are linked with the altered expression and function of D3 and D4 receptors. Modulation of the function of D3 or D4 receptors in the immune system opens new opportunities in disease

Generation of subtype-selective 1,4-disubstituted aromatic piperazines and piperidines (1,4-DAPs) and their applications in drug discovery

Most of the highly potent and top-selling antipsychotic drugs (including the D2/D3/D4 receptor antagonist haloperidol) belong to the group of 1,4-DAPs. This privileged structure proved to be an extremely valuable recognition element because it binds not only dopamine receptors but also other monoamine GPCRs. For example, the 1,4-DAP risperidone displays high affinity to D2, D3, D4, 5-hydroxytryptomine (5-HT2), α1 adrenergic and histamine (H1) receptors. The 1,4-DAP aripiprazole, which in 2002

Beyond the 1,4-DAP family

Although the 1,4-DAP moiety has proven to be a very potent recognition element, there have been successful attempts for a structural evolution of this pharmacophore (Table 3, Figure 2). All these lead optimization programs resulted in a formal structural rearrangement of the phenylpiperazine moiety to afford ring systems that feature an aminoethylene unit attached to the π-system of the head group. The aminothiazole 1 (which can be regarded as a ligation product of the D3 agonist pramipexole

Functional selectivity

In the past 15 years, substantial information has demonstrated that ligands can stabilize individual global ensembles of receptor conformations and that different signaling proteins interact with distinct parts of GPCRs [73]. It became obvious that the classification of agonist/partial agonist/antagonist is not sufficient for the description of the intrinsic activity of a ligand. Functional investigations of classical dopaminergic agents indicated that propylnorapomophine, dinapsoline,

Monomer/dimer selectivity

Over the past decade, evidence has accumulated to suggest that GPCRs can function as dimers or large oligomers. Communication between protomers of D2 receptors has been proven to modulate GPCR activation in transfected cell lines [78]. An elegant approach from Durroux and coworkers demonstrated the presence of oxytocin receptor dimers and oligomers in native tissue using a time-resolved Förster resonance energy transfer (FRET) strategy based on receptor labeling with selective fluorescent

Perspectives and conclusion

Within the last few years, the rational design of subtype-selective dopamine D3 and D4 receptor ligands has become feasible. The development of D3-selective agonists, functionally selective ligands, and the exploitation of homo- and heteromer formation remains challenging.

Planning to solve at least three co-crystal structures per target of its complex with a relevant ligand, the Center of Membrane Protein Structure Determination (CMPD) aims to develop a better understanding of the

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