Synthesis, in silico, and in vitro studies of novel dopamine D2and D3receptor ligands (original) (raw)
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Synthesis, in silico, and in vitro studies of novel dopamine D 2 and D 3 receptor 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]).
Journal of Medicinal Chemistry, 2011
N-(3-fluoro-4-(4-(2,3-dichloro-or 2-methoxyphenyl)piperazine-1-yl)-butyl)-aryl carboxamides were prepared and evaluated for binding and function at dopamine D3 (D3R) and D2 receptors (D2R). In this series, we discovered some of the most D3R selective compounds reported to date, (e.g. 8d and 8j >1000-fold D3R-selective over D2R.) In addition, chimeric receptor studies further identified the second extracellular (E2) loop as an important contributor to D3R binding selectivity. Further, compounds lacking the carbonyl group in the amide linker were synthesized and while these amine-linked analogues bound with similar affinities to the amides at D2R, this modification dramatically reduced binding affinities at D3R by >100-fold (e.g. D3RKi for 15b = 393 v. for 8j = 2.6 nM) resulting in compounds with significantly reduced D3R selectivity. This study supports a pivotal role for the D3R E2 loop and the carbonyl group in the 4phenylpiperazine class of compounds and further reveals a point of separation between structureactivity relationships at D3R and D2R.
Research Journal of Pharmaceutical, Biological and Chemical Sciences
An analysis of the relationships between electronic structure and dopamine D 2 receptor binding affinity was carried out for a series of [4-(4-carboxamidobutyl)]-1-arylpiperazines. Local atomic reactivity indices were obtained at the B3LYP/6-31G(d,p) level after full geometry optimization. A statistically significant equation relating several local atomic reactivity indices with the binding affinity was obtained. From the results, a partial 2D pharmacophore is built, containing several sites that can be used for substitution enhancing binding affinity. An important conclusion is that because the common skeleton hypothesis is producing once more excellent results, the results reported here must serve as a guide for correct docking procedures.
Bivalent molecular probes for dopamine D2-like receptors
Bioorganic & Medicinal Chemistry, 2012
Merging two arylamidoalkyl substituted phenylpiperazines as prototypical recognition elements for dopamine D 2 -like receptors by oligoethylene glycol linkers led to a series of bivalent ligands. These dimers were investigated in comparison to their monomeric analogues for their dopamine D 2long , D 2short , D 3 and D 4 receptor binding. Radioligand binding experiments revealed strong bivalent effects for some para-substituted benzamide derivatives. For the D 3 subtype, the target compounds 32, 34 and 36 showed an up to 70-fold increase of affinity and a substantial enhancement of subtype selectivity when compared to the monovalent analogue 24. Analysis of the binding curves displayed Hill slopes very close to one indicating that the bivalent ligands displace 1 equiv of radioligand. Obviously, the two pharmacophores occupy an orthosteric and an allosteric binding site rather than adopting a receptor-bridging binding mode.
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.
ACS Omega
The search for synthetic selective compounds for G-protein-coupled receptors has provided a myriad of molecules with high selectivity and therapeutic potential. In some cases, however, selectivity is difficult to obtain. For instance, the selectivity ratio is relatively low for compounds acting on D 2 and D 3 dopamine receptors, which are targets of neurodegenerative diseases such as Parkinson's and Huntington's. From a therapeutic point of view, it is of interest the relative recent discovery of biased agonism, which is characterized by different signaling pathways engaged by different compounds acting on a given receptor. The aim of this paper was to investigate whether new piribedil-derived compounds could display higher selectivity for D 2 or D 3 receptor and/or provide biased signaling. The results show that selectivity was not different, but that one of the molecules described here, 5-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)quinolin-8-ol (10), does engage Gi-mediated signaling via D 2 or D 3 receptors, whereas it does not activate the mitogen-activated-protein kinase pathway, which is usually activated by dopamine receptor agonists.
Biochemical Pharmacology, 2011
Dopamine (DA) receptors have been targeted for drug development for the treatment of various Central Nervous System (CNS)-related psychiatric illnesses, neurodegeneration, drug abuse, and other disorders [1,2]. DA receptors belong to a class of G-protein coupled receptors (GPCRs), are found in the CNS and in the periphery [3], and can be classified as being either D 1-like or D 2-like. The D1 and D5 subtypes belong to the D 1-like class, and the D2, D3, and D4 subtypes are D 2-like receptors. These classifications have been made on the basis of receptor pharmacology and function. Both D 1-like and D 2-like DA receptors share the same effector molecule, adenylate cyclase. Upon receptor activation, D 1like receptors activate adenylate cyclase, whereas D 2-like receptors inhibit it [4].