Discovery of selective dopamine D4 receptor antagonists: 1-Aryloxy-3-(4-aryloxypiperidinyl)-2-propanols (original) (raw)
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Identification of a new selective dopamine D4 receptor ligand
Bioorganic & Medicinal Chemistry, 2014
The dopamine D 4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D 4 ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective and increased affinity to the DAD 4 receptor subtype, in comparison to its piperidine analog. This led to further exploration of the piperazine moiety to identify new agents that are selective at the D 4 receptor. Compound 27 (K i D 4 = 0.84 nM) was the most potent of the compounds tested. However, it only had moderate selectivity for the D 4 receptor. Compound 28 (K i D 4 = 3.9 nM) while not as potent, was more discriminatory for the D 4 receptor subtype. In fact, compound 28 has little or no binding affinity to any of the other four DA receptor subtypes. In addition, of the 23 CNS receptors evaluated, only two, 5HT 1A R and 5HT 2B R, have binding affinity constants better than 100 nM (Ki < 100 nM). Compound 28 is a potentially useful D 4-selective ligand for probing disease treatments involving the D 4 receptor, such as assisting smoking cessation, reversing cognitive deficits in schizophrenia and treating erectile dysfunction. Thus, further optimization, functional characterization and evaluation in animal models may be warranted.
The discovery of PD 89211 and related compounds: Selective dopamine D4 receptor antagonists
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2002
The dopamine (DA) D2 family of receptors consists of the D2, D3, and D4 receptors. The DA D4 receptor is of interest as a target for drugs to treat schizophrenia based upon its high affinity for the atypical antipsychotic clozapine and its localization to the limbic and cortical regions of the brain. As part of a program to identify novel DA D4 receptor antagonists, a high-volume screen using the Parke-Davis compound library was initiated. This led to the discovery of PD 89211 (benzenemethanol, 2-chloro-4-[4-[(1H-benzimidazol-2-yl)methyl]-1piperzinyl]) that displaced [ 3 H]spiperone binding to hD4.2 with an affinity (K i ) of 3.7 nM. PD 89211 exhibited high selectivity for the DA D4.2 receptor ( > 800-fold) as compared to other hDA receptor subtypes, rat brain serotonin, and adrenergic receptors. In vitro, PD 89211 had D4 receptor antagonist activity reversing quinpirole-induced [ 3 H]thymidine uptake in CHOpro5 cells (IC 50 = 2.1 nM). Limited structureactivity relationship (SAR) studies indicated that compounds with a 4-chloro-, 4-methyl-, and 3-chloro-substituents on the phenyl ring retained high affinity for D4 receptors, while those with a 4-methoxy-and no substituent had less affinity. While all clinically effective antipsychotics increase DA synthesis (DOPA accumulation) in rodents, PD 89211 did not increase DA synthesis in the DA-enriched striatum, indicating no effect on DA turnover and low propensity for exhibiting motor side effects. However, it did increase catecholamine synthesis in rat hippocampus, as did clozapine. Moreover, PD 89211 selectivity increased catecholamine synthesis in the hippocampus of wild type but not in mice lacking D4 receptors, suggesting that one function of D4 receptors may be to modulate DA/norepinephrine (NE) turnover in this brain area known to possess D4 receptors. The discovery of compounds like PD 89211 provides a tool to help in understanding the function of DA D4 receptors in the CNS. D
Bioorganic & Medicinal Chemistry Letters, 2001
AbstractÐThe synthesis of the two enantiomers of 3-(3,4-dimethylphenyl)-1-propylpiperidine 1, a potent and selective D4 dopaminergic ligand, was performed. The 3-(3,4-dimethylphenyl)-1-propylpiperidine with the R con®guration showed an anity for the D4 receptors 6-fold higher than the corresponding enantiomer with the S con®guration. Furthermore, the (R)-1 enantiomer proved to be highly selective for D4 receptors with respect to D2±D3 receptors, with a K i ratio higher than 25,000, while the (S)-1 enantiomer was about 100-fold less selective than the (R)-1 one #
Journal of Medicinal Chemistry, 2019
The dopamine D 4 receptor (D 4 R) plays important roles in cognition, attention, and decision making. Novel D 4 R-selective ligands have promise in medication development for neuropsychiatric conditions, including Alzheimer's disease and substance use disorders (SUD). To identify new D 4 R-selective ligands, and to understand the molecular determinants of agonist efficacy at D 4 R, we report a series of eighteen novel ligands based on the classical D 4 R 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, cAMP inhibition assays, and molecular dynamic computational modeling. We identified several novel D 4 Rselective (K i ≤ 4.3 nM and >100-fold vs. other D 2-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 D 2-like receptors and may provide insights to targeted drug discovery leading to a better understanding of the role of D 4 Rs in neuropsychiatric disorders.
Bioorganic & Medicinal Chemistry Letters, 2006
Aminomethyl-substituted biaryls bearing a pyrazole or triazole moiety were synthesized and investigated for dopamine and serotonin receptor binding. The N-arylpyrazoles 3b,f,g and 4 revealed K i values in the subnanomolar range (0.28-0.70 nM) for the dopamine D4 receptor subtype. Employing both mitogenesis and GTPcS assays, ligand efficacy was evaluated indicating partial agonist properties. Interestingly, the tetrahydropyrimidine 4 (FAUC 2020) displayed significant intrinsic selectivity for D2 long over D2 short .
Synthesis, in silico, and in vitro studies of novel dopamine D2and D3receptor ligands
Archiv Der Pharmazie, 2021
Dopamine is an important neurotransmitter in the human brain and its altered concentrations can lead to various neurological diseases. We studied the binding of novel compounds at the dopamine D 2 (D 2 R) and D 3 (D 3 R) receptor subtypes, which belong to the D 2-like receptor family. The synthesis, in silico, and in vitro characterization of 10 dopamine receptor ligands were performed. Novel ligands were docked into the D 2 R and D 3 R crystal structures to examine the precise binding mode. A quantum mechanics/molecular mechanics study was performed to gain insights into the nature of the intermolecular interactions between the newly introduced pentafluorosulfanyl (SF 5) moiety and D 2 R and D 3 R. A radioligand displacement assay determined that all of the ligands showed moderate-to-low nanomolar affinities at D 2 R and D 3 R, with a slight preference for D 3 R, which was confirmed in the in silico studies. N-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-4-(pentafluoro-λ6-sulfanyl)benzamide (7i) showed the highest D 3 R affinity and selectivity (pK i values of 7.14 [D 2 R] and 8.42 [D 3 R]).
The naphtosultam derivative RP 62203 (fananserin) has high affinity for the dopamine D 4 receptor
European Journal of Pharmacology, 1996
The dopamine D 4 receptor is a potential target for novel antipsychotic drugs. Most available compounds with affinity for the dopamine D 4 receptor also bind to dopamine D 2 receptors. This report describes the affinity of the 5-HT2A receptor antagonist RP 62203 (fananserin) for the human dopamine D 4 receptor. Fananserin displaces [3H]spiperone binding to recombinant human dopamine D 4 receptors with a K i of 2.93 nM. This compares with an affinity (K i) of 0.37 nM for the rat 5-HT2A receptor and of 726 nM for the rat dopamine D e receptor.
NGB 2904 and NGB 2849: Two highly selective dopamine D3 receptor antagonists
Bioorganic & Medicinal Chemistry Letters, 1998
N-(4-[4-{2, 3-dichlorophenyl}-l-piperazinyl]butyl)-3-fluorenylcarboxamide and N-(4-[4-{2, 3-dichlorophenyl }-1-piperazinyl]butyl)-2-biphenylenylcarboxamide were prepared in several steps from 2,3-dichloroaniline. These compounds were identified as highly selective dopamine D3 receptor antagonists.
Journal of Medicinal Chemistry, 2003
We have previously reported that compounds dimethyl-substituted on the phenyl ring of N-npropyl-3-phenylpiperidines (PPEs) have a high (nM) affinity and selectivity toward the D 4 dopamine receptor (D 4 DAR) with m,p-dimethyl PPE (1) having the highest affinity and selectivity. In the present paper we have investigated the role of the methyl substitution by the synthesis of monomethylated (2a-c) and nonmethylated (2d) PPEs followed by the characterization of their biological properties using receptor binding assays. Our findings reveal that the methyl substitution of the phenyl ring is not necessary for a high and selective binding affinity to the D 4 DAR. Moreover, we have also synthesized cyclohexylpiperidines (CHPEs, 3a-d), which all showed higher binding affinities for the D 4 DAR than their aromatic counterparts. These results indicate that a π-π type interaction of the phenyl ring of PPEs with the D 4 DAR might not be essential, whereas a simple hydrophobic attraction between the cyclohexyl substituent of CHPEs and a hypothesized lipophilic pocket of the receptor might be crucial. Furthermore, functional assays indicate that 3d, as well as 1, are partial agonist at the D 4 DAR and therefore might represent new pharmacological tools to investigate the role of D 4 DAR activation in the control of cognitive functions and emotional states in health and disease.
Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands
Bioorganic & Medicinal Chemistry Letters, 2009
A series of new benzolactam derivatives was synthesized and the derivatives were evaluated for their affinities at the dopamine D 1 , D 2 , and D 3 receptors. Some of these compounds showed high D 2 and/or D 3 affinity and selectivity over the D 1 receptor. The SAR study of these compounds revealed structural characteristics that decisively influenced their D 2 and D 3 affinities. Structural models of the complexes between some of the most representative compounds of this series and the D 2 and D 3 receptors were obtained with the aim of rationalizing the observed experimental results. Moreover, selected compounds showed moderate binding affinity on 5-HT 2A which could contribute to reducing the occurrence of extrapyramidal side effects as potential antipsychotics.