Novel cyclohexyl amides as potent and selective D 3 dopamine receptor ligands (original) (raw)
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Synthesis and evaluation of amides surrogates of dopamine D3 receptor ligands
Bioorganic & Medicinal Chemistry Letters, 2010
Isosteric replacement of the amide function and modulation of the arylpiperazine moiety of known dopamine D3 receptor ligands led to potent and selective compounds. Enhanced bioavailability and preferential brain distribution make compound 6c a good candidate for pharmacological and clinical evaluation.
Bioorganic & Medicinal Chemistry, 2005
A series of N-(2-methoxyphenyl)piperazine and N-(2,3-dichlorophenyl)piperazine analogs were prepared and their affinities for dopamine D 2 , D 3 , and D 4 receptors were measured in vitro. Binding studies were also conducted to determine if the compounds bound to sigma (r 1 and r 2 ) and serotonin (5-HT 1A , 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 , and 5-HT 7 ) receptors. The results of the current study revealed a number of compounds (12b, 12c, 12e, and 12g) having a high affinity for D 3 (K i at D 3 receptors ranging from 0.3 to 0.9 nM) versus D 2 (K i at D 2 receptors ranging from 40 to 53 nM) receptors and a log P value indicating that they should readily cross the blood brain barrier (log P = 2.6-3.5). All of the compounds evaluated in this study had a high affinity for serotonin 5-HT 1A receptors. These compounds may be useful as probes for studying the behavioral pharmacology of the dopamine D 3 receptor, as well as lead compounds for the development of radiotracers for studying D 3 receptor regulation in vivo with the functional imaging technique, positron emission tomography.
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.
Journal of Medicinal Chemistry, 2005
Dopamine D3 receptor subtypes have been hypothesized to play a pivotal role in modulating the reinforcing and drug-seeking effects induced by cocaine. However, definitive pharmacological investigations have been hampered by the lack of highly D3 receptor selective compounds that can be used in vivo. To address this problem, the potent and D3-receptor-selective antagonist NGB 2904 (1, 9H-fluorene-2-carboxylic acid {4-[(2,3-dichlorophenyl)-piperazin-1-yl]-butyl}amide, K i (hD3)) 2.0 nM, K i (hD2 L)) 112 nM, D2/D3 selectivity ratio of 56) was chosen as a lead structure for chemical modification in an attempt to reduce its high lipophilicity (c log D) 6.94) while optimizing D3 receptor binding affinity and D2/D3 selectivity. A series of >30 novel analogues were synthesized, and their binding affinities were evaluated in competition binding assays in HEK 293 cells transfected with either D2 L , D3, or D4 human dopamine receptors using the high affinity, selective D2-like receptor antagonist 125 I-IABN. Structural diversity in the aryl amide end of the molecule was found to have a major influence on (sub)nanomolar D3 receptor affinity and D2/D3 selectivity, which was optimized using a more rigid trans-butenyl linker between the aryl amide and the piperazine. Several analogues demonstrated superior D3 receptor binding affinities and selectivities as compared to the parent ligand. Compound 29 (N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide) displayed the most promising pharmacological profile (K i (hD3)) 0.7 nM, K i (hD2 L)) 93.3 nM, D2/D3 selectivity ratio of 133). In addition, this ligand inhibited quinpirole stimulation of mitogenesis at human dopamine D3 receptors transfected into Chinese hamster ovary (CHO) cells, with an EC 50 value of 3.0 nM. Compound 29 was a nearly 5 times more potent antagonist at the D3 receptor than 1 (EC 50) 14.4 nM). Moreover, a decrease in c log D value of ∼2 orders of magnitude was determined for this novel D3-receptor-preferring ligand, compared to 1. In summary, chemical modification of 1 has resulted in compounds with high affinity and selectivity for D3 receptors. The most promising candidate, compound 29, is currently being evaluated in animal models of cocaine abuse and will provide an important tool with which to elucidate the role of D3 receptors in drug reinforcement in vivo.
Bioorganic & Medicinal Chemistry Letters, 2003
The dopamine D 3 receptor subtype has been targeted as a potential neurochemical modulator of the behavioral actions of psychomotor stimulants, such as cocaine. Previous synthetic studies provided structural requirements for high affinity binding to D 3 receptors which included a 2,3-dichloro-phenylpiperazine linked to an arylamido function via a butyl chain. To reduce lipophilicity of these agents and further investigate optimal conformation, a second series of 15 novel ligands was designed that included heteroaromatic substitution and unsaturated alkyl linkers. These compounds were synthesized and evaluated for binding at rat D 3 and D 2 receptors stably expressed in Sf9 cells. D 3 binding affinities ranged from K i =0.6-1080 nM, with a broad range of D 3 /D 2 selectivities (2-97). The discovery of potent, selective and bioavailable D 3 receptor ligands will provide essential molecular probes to elucidate the role D 3 receptors play in the psychomotor stimulant and reinforcing effects of cocaine.
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]).
MedChemComm, 2013
A series of substituted 1H-indolyl carboxylic acid amides that contain a N-(2methoxyphenyl)piperazine or N-(2-fluoroethoxy)piperazine group were synthesized and their affinities for human dopamine D 2 , D 3 , and D 4 receptors were determined. Two of these compounds, 14a and 14b, displayed high binding affinity at D 3 (K i = 0.18 and 0.4 nM, respectively), and selectivity for D 3 vs. D 2 receptors (87-fold and 60-fold, respectively). These two compounds had low binding affinity at D 4 receptors and receptor sites. The intrinsic activity of these compounds at D 2 and D 3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay; both 14a and 14b were found to be partial agonists. Furthermore, for compound 14a, the log D value of 2.85 suggested it has suitable lipophilicity for crossing the blood-brain-barrier. † Electronic supplementary information (ESI) available. See
Molecular Pharmacology, 2004
We previously demonstrated that, in the D4 dopamine receptor, the aromatic microdomain that spans the interface of the second and third transmembrane segments influences the high-affinity interactions with the D4-selective ligand L750,667 [3-{[4-(4-iodophenyl) piperazin-1yl]methyl}-1H-pyrrolo[2,3-b]pyridine] and the D2-selective ligands methyl-spiperone, aripiprazole, and its congener OPC4392 [7-[3-(4-(2,3-dimethylphenyl) piperazinyl) propoxy] 2-(1H)-quinolinone] . Here we tested a variety of 1,4-disubstituted aromatic piperidines/piperazines (1,4-DAPs) with different subtype selectivities and functional properties against a panel of D4 receptor mutations in the aromatic microdomain to ascertain whether these ligands recognize this common site. Mutant D4 receptors were constructed by substituting the nonconserved amino acid(s) from the corresponding locations in the D2 receptor. The D4-L2.60W, D4-F2.61V, and D4-LM3.28-3.29FV substitutions result in alterations of the relative position of members of the aromatic microdomain. From these results and molecular models of the ligand-receptor complexes, we conclude that 9 of the 11 D4-selective 1,4-DAPs, including L750,667, have a common pattern of ligand-receptor recognition that depends upon favorable interactions with the phenylalanine at position 2.61 (D4-F2.61V, 20-96-fold decrease). Like methylspiperone, aripiprazole, and OPC4392, the two D4-selective 1,4-DAPs that are insensitive to the D4-F2.61V mutation are sensitive to aromatics at position 2.60 (D4-L2.60W, 7-20-fold increase), and they all have longer spacer arms that permit their tethered aromatics to adopt alternative orientations in the binding-site crevice. All 11 of the D4-selective 1,4-DAPs were sensitive to the D4-LM3.28-3.29FV mutation (13-494-fold decrease) but not the moderately D2selective methyl-spiperone. The inferences suggest that subtype selectivity involves two different modes of interaction with the microdomain for the D4-selective 1,4-DAPs and a third mode for D2-selective 1,4-DAPs.
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.