Trends in Pharmacological Sciences
ReviewRecent advances in the search for D3- and D4-selective drugs: probes, models and candidates
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
References (97)
- et al.
Molecular biology of dopamine receptors
Trends Pharmacol. Sci.
(1992) - et al.
The structural evolution of dopamine D3 receptor ligands: structure-activity relationships and selected neuropharmacological aspects
Pharmacol. Ther.
(2006) The dopamine receptor family: molecular biology and pharmacology
Semin. Neurosci.
(1992)- et al.
Dopamine D3 receptor agonists for protection and repair in Parkinson's disease
Curr. Opin. Pharmacol.
(2007) The dopamine D3 receptor and drug dependence: effects on reward or beyond?
Neuropharmacology
(2005)Effectiveness of the selective D4 antagonist sonepiprazole in schizophrenia: a placebo-controlled trial
Biol. Psychiatry
(2004)Dopamine receptor D4 polymorphism predicts the effect of L-DOPA on gambling behavior
Biol. Psychiatry
(2010)Neurotransmitters activate T-cells and elicit crucial functions via neurotransmitter receptors
Curr. Opin. Pharmacol.
(2008)Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands
Bioorg. Med. Chem. Lett.
(2009)CoMFA and CoMSIA investigations of dopamine D3 receptor ligands leading to the prediction, synthesis and evaluation of rigidized FAUC 365 analogues
Bioorg. Med. Chem.
(2006)
Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance
Curr. Opin. Pharmacol.
High-resolution crystal structure of an engineered human beta 2-adrenergic G protein-coupled receptor
Science
Recent progress in development of dopamine receptor subtype-selective agents: potential therapeutics for neurological and psychiatric disorders
Chem. Rev.
Selective dopamine D3 receptor antagonists. a decade of progress: 1997–2007
Expert Opin. Ther. Pat.
Dopamine D4 receptor antagonists
Curr. Pharm. Des.
How many drug targets are there?
Nat. Rev. Drug. Discov.
All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2 receptors
CNS Neurosci. Ther.
Dopamine Receptor Subtype-Selective Drugs: D2-Like Receptors
The D3 dopamine receptor: neurobiology and potential clinical relevance
Pharmacol. Rev.
Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics
Nature
Selective Antagonism at dopamine D3 receptors enhances monoaminergic and cholinergic neurotransmission in the rat anterior cingulate cortex
Neuropsychopharmacol.
S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b- tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent: iii. actions in models of therapeutic activity and induction of side effects
J. Pharmacol. Exp. Ther.
The dopamine D(3) receptor antagonist, S33138, counters cognitive impairment in a range of rodent and primate procedures
Int. J. Neuropsychopharmacol.
Amino acid substitution in the dopamine D3 receptor as a useful polymorphism for investigating psychiatric disorders
Psychiatr. Genet.
A functional variant of the dopamine D3 receptor is associated with risk and age-at-onset of essential tremor
Proc. Natl. Acad. Sci. U.S.A.
Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research, pharmacogenetics and pharmacogenomics of schizophrenia
Mol. Psychiatry
Homozygosity for the Gly-9 variant of the dopamine D3 receptor and risk for tardive dyskinesia in schizophrenic patients
Int. J. Neuropsychopharmacol.
The dopamine D3/D2 agonist (+)-PD-128,907 [(R-(+)- trans-3,4a,10b-Tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin- 9-ol)] protects against acute and cocaine-kindled seizures in mice: further evidence for the involvement of D3 receptors
J. Pharmacol. Exp. Ther.
A functional role for the dopamine D3 receptor in the induction and expression of behavioural sensitization to ethanol in mice
Psychopharmacol.
Decreased binding of the D3 dopamine receptor- preferring ligand [11C]-(+)-PHNO in drug-naïve Parkinson's disease
Brain
Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine
Nature
Regulation of NMDA receptors by dopamine D4 signaling in prefrontal cortex
J. Neurosci.
The dopamine D4 receptor: biochemical and signalling properties
Cell Mol. Life Sci.
Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder
Arch. Gen. Psychiatry
Novelty seeking and the dopamine D4 receptor gene (DRD4) revisited in asians: haplotype characterization and relevance of the 2-repeat allele
Am. J. Med. Genet. Part B
Impulse control disorders in parkinson disease. A cross-sectional study of 3090 patients
Arch. Neurol.
Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats
Proc. Natl. Acad. Sci. U.S.A.
Cutting edge: stimulation of dopamine D4 receptors induce T cell quiescence by up-regulating Krüppel-like factor-2 expression through Inhibition of ERK1/ERK2 phosphorylation
J. Immunol.
Effect of dopamine D3 receptor blockade on renal function and glomerular size in diabetic rats
Naunyn-Schmiedebergs Arch. Pharmacol.
D4 dopamine receptor enhances angiotensin II- stimulated aldosterone secretion through PKC-ɛ and calcium signaling
Am. J. Physiol. Endocrinol. Metab.
Amphetamines induce tissue factor and impair tissue factor pathway inhibitor: role of dopamine receptor type 4
Eur. Heart J.
Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles
Mol. Psychiatry
Aripiprazole acts as a selective dopamine D2 receptor partial agonist
Expert Opin. Investig. Drug
Interactive SAR studies: rational discovery of super- potent and highly selective dopamine D3 receptor antagonists and partial agonists
J. Med. Chem.
Progress in developing D3 dopamine receptor ligands as potential therapeutic agents for neurological and neuropsychiatric disorders
Curr. Pharm. Des.
Structure-affinity relationship study on N-[4-(4- arylpiperazin-1-yl)butyl]arylcarboxamides as potent and selective dopamine D3 receptor ligands
J. Med. Chem.
N-(omega-(4-(2-methoxyphenyl)piperazin-1- yl)alkyl)carboxamides as dopamine D2 and D3 receptor ligands
J. Med. Chem.
Dopamine D3 receptor partial agonists and antagonists as potential drug abuse therapeutic agents
J. Med. Chem.
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