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Journal articles on the topic 'Bitopic ligand'

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Author: Grafiati

Published: 10 March 2023

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1

Gao, Zhan-Guo, Kiran S. Toti, Ryan Campbell, R. Rama Suresh, Huijun Yang, and Kenneth A. Jacobson. "Allosteric Antagonism of the A2A Adenosine Receptor by a Series of Bitopic Ligands." Cells 9, no. 5 (May 12, 2020): 1200. http://dx.doi.org/10.3390/cells9051200.

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Allosteric antagonism by bitopic ligands, as reported for many receptors, is a distinct modulatory mechanism. Although several bitopic A2A adenosine receptor (A2AAR) ligand classes were reported as pharmacological tools, their receptor binding and functional antagonism patterns, i.e., allosteric or competitive, were not well characterized. Therefore, here we systematically characterized A2AAR binding and functional antagonism of two distinct antagonist chemical classes. i.e., fluorescent conjugates of xanthine amine congener (XAC) and SCH442416. Bitopic ligands were potent, weak, competitive or allosteric, based on the combination of pharmacophore, linker and fluorophore. Among antagonists tested, XAC, XAC245, XAC488, SCH442416, MRS7352 showed Ki binding values consistent with KB values from functional antagonism. Interestingly, MRS7396, XAC-X-BY630 (XAC630) and 5-(N,N-hexamethylene)amiloride (HMA) were 9–100 times weaker in displacing fluorescent MRS7416 binding than radioligand binding. XAC245, XAC630, MRS7396, MRS7416 and MRS7322 behaved as allosteric A2AAR antagonists, whereas XAC488 and MRS7395 antagonized competitively. Schild analysis showed antagonism slopes of 0.42 and 0.47 for MRS7396 and XAC630, respectively. Allosteric antagonists HMA and MRS7396 were more potent in displacing [3H]ZM241385 binding than MRS7416 binding. Sodium site D52N mutation increased and decreased affinity of HMA and MRS7396, respectively, suggesting possible preference for different A2AAR conformations. The allosteric binding properties of some bitopic ligands were rationalized and analyzed using the Hall two-state allosteric model. Thus, fluorophore tethering to an orthosteric ligand is not neutral pharmacologically and may confer unexpected properties to the conjugate.

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2

Ferrisi, Rebecca, Beatrice Polini, Caterina Ricardi, Francesca Gado, Kawthar A. Mohamed, Giovanna Baron, Salvatore Faiella, et al. "New Insights into Bitopic Orthosteric/Allosteric Ligands of Cannabinoid Receptor Type 2." International Journal of Molecular Sciences 24, no. 3 (January 21, 2023): 2135. http://dx.doi.org/10.3390/ijms24032135.

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Very recently, we have developed a new generation of ligands targeting the cannabinoid receptor type 2 (CB2R), namely JR compounds, which combine the pharmacophoric portion of the CB2R positive allosteric modulator (PAM), EC21a, with that of the CB2R selective orthosteric agonist LV62, both synthesized in our laboratories. The functional examination enabled us to identify JR14a, JR22a, and JR64a as the most promising compounds of the series. In the current study, we focused on the assessment of the bitopic (dualsteric) nature of these three compounds. Experiments in cAMP assays highlighted that only JR22a behaves as a CB2R bitopic (dualsteric) ligand. In parallel, computational studies helped us to clarify the binding mode of these three compounds at CB2R, confirming the bitopic (dualsteric) nature of JR22a. Finally, the potential of JR22a to prevent neuroinflammation was investigated on a human microglial cell inflammatory model.

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Adhikari, Pramisha, Bing Xie, Ana Semeano, Alessandro Bonifazi, Francisco O. Battiti, Amy H. Newman, Hideaki Yano, and Lei Shi. "Chirality of Novel Bitopic Agonists Determines Unique Pharmacology at the Dopamine D3 Receptor." Biomolecules 11, no. 4 (April 13, 2021): 570. http://dx.doi.org/10.3390/biom11040570.

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The dopamine D2/D3 receptor (D2R/D3R) agonists are used as therapeutics for Parkinson’s disease (PD) and other motor disorders. Selective targeting of D3R over D2R is attractive because of D3R’s restricted tissue distribution with potentially fewer side-effects and its putative neuroprotective effect. However, the high sequence homology between the D2R and D3R poses a challenge in the development of D3R selective agonists. To address the ligand selectivity, bitopic ligands were designed and synthesized previously based on a potent D3R-preferential agonist PF592,379 as the primary pharmacophore (PP). This PP was attached to various secondary pharmacophores (SPs) using chemically different linkers. Here, we characterize some of these novel bitopic ligands at both D3R and D2R using BRET-based functional assays. The bitopic ligands showed varying differences in potencies and efficacies. In addition, the chirality of the PP was key to conferring improved D3R potency, selectivity, and G protein signaling bias. In particular, compound AB04-88 exhibited significant D3R over D2R selectivity, and G protein bias at D3R. This bias was consistently observed at various time-points ranging from 8 to 46 min. Together, the structure-activity relationships derived from these functional studies reveal unique pharmacology at D3R and support further evaluation of functionally biased D3R agonists for their therapeutic potential.

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4

Niklas, Beata, Bruno Lapied, and Wieslaw Nowak. "In Search of Synergistic Insect Repellents: Modeling of Muscarinic GPCR Interactions with Classical and Bitopic Photoactive Ligands." Molecules 27, no. 10 (May 20, 2022): 3280. http://dx.doi.org/10.3390/molecules27103280.

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Insect vector-borne diseases pose serious health problems, so there is a high demand for efficient molecules that could reduce transmission. Using molecular docking and molecular dynamics (MD) simulation, we studied a series of compounds acting on human and insect muscarinic acetylcholine receptors (mAChRs), a novel target of synergistic agents in pest control. We characterized early conformational changes of human M1 and fruit fly type-A mAChR G protein-coupled receptors (GPCRs) in response to DEET, IR3535, and muscarine binding based on the MD analysis of the activation microswitches known to form the signal transduction pathway in class A GPCRs. We indicated groups of microswitches that are the most affected by the presence of a ligand. Moreover, to increase selectivity towards insects, we proposed a new, bitopic, photoswitchable mAChR ligand—BQCA-azo-IR353 and studied its interactions with both receptors. Modeling data showed that using a bitopic ligand may be a promising strategy in the search for better insect control.

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5

Cooper, Samantha Louise, Edward Wragg, Julie March, Stephen Hill, and Jeanette Woolard. "Effects of an Adenosine Receptor Bitopic Ligand on The Cardiovascular System." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.02426.

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6

Keov, Peter, Laura López, Shane M. Devine, Celine Valant, J. Robert Lane, Peter J. Scammells, Patrick M. Sexton, and Arthur Christopoulos. "Molecular Mechanisms of Bitopic Ligand Engagement with the M1Muscarinic Acetylcholine Receptor." Journal of Biological Chemistry 289, no. 34 (July 8, 2014): 23817–37. http://dx.doi.org/10.1074/jbc.m114.582874.

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7

Reger, Daniel L., Russell P. Watson, and Mark D. Smith. "An Organoplatinum(II) Complex of a Bitopic, Propylene-linked Bis(pyrazolyl)methane Ligand." Journal of Chemical Crystallography 38, no. 1 (October 24, 2007): 17–20. http://dx.doi.org/10.1007/s10870-007-9264-z.

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8

Reger, Daniel L., Andrea E. Pascui, and Mark D. Smith. "Structural Variations in Copper(II) Complexes of a Bitopic Bis(pyrazolyl)methane Ligand." European Journal of Inorganic Chemistry 2012, no. 29 (May 25, 2012): 4593–604. http://dx.doi.org/10.1002/ejic.201200118.

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9

Lider, Sukhikh, Smolentsev, Semitut, Filatov, and Potapov. "Synthesis, Crystal Structure, Thermal Analysis, and DFT Calculations of Molecular Copper(II) Chloride Complexes with Bitopic Ligand 1,1,2,2-tetrakis(pyrazol-1-yl)ethane." Crystals 9, no. 4 (April 24, 2019): 222. http://dx.doi.org/10.3390/cryst9040222.

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Two binuclear coordination compounds of Cu(II) chloride with the bitopic ligand 1,1,2,2-tetrakis(pyrazol-1-yl)ethane (Pz4) of the composition [Cu2(µ2Pz4)(DMSO)2Cl4]·4H2O and [Cu2(µ2Pz4)(DMSO)2Cl4]∙2DMSO were prepared and characterized by elemental analysis, IR spectroscopy, thermogravimetric analysis, single-crystal X-ray diffraction, and powder diffraction analysis. It was shown that in contrast to silver(I) and copper(II) nitrates, copper(II) chloride forms discrete complexes instead of coordination polymers. The supramolecular structure of the complex [Cu2(µ2Pz4)(DMSO)2Cl4]·4H2O with lattice water molecules is formed by OH···Cl and OH···O hydrogen bonds. Density functional theory (DFT) calculations of vibrational frequencies of the ligand and its copper(II) complex allowed for assigning IR bands to specific vibrations.

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10

Lee, Boeun, Michelle Taylor, Suzy A. Griffin, Tamara McInnis, Nathalie Sumien, Robert H. Mach, and Robert R. Luedtke. "Evaluation of Substituted N-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands." Molecules 26, no. 11 (May 26, 2021): 3182. http://dx.doi.org/10.3390/molecules26113182.

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N-phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compounds was found to be consistent with their ability to bind at the D3 dopamine receptor subtype in a bitopic manner. In this study, a series of the 3-thiophenephenyl and 4-thiazolylphenyl fluoride substituted N-phenylpiperazine analogs were evaluated. Compound 6a was found to bind at the human D3 receptor with nanomolar affinity with substantial D3 vs. D2 binding selectivity (approximately 500-fold). Compound 6a was also tested for activity in two in-vivo assays: (1) a hallucinogenic-dependent head twitch response inhibition assay using DBA/2J mice and (2) an L-dopa-dependent abnormal involuntary movement (AIM) inhibition assay using unilateral 6-hydroxydopamine lesioned (hemiparkinsonian) rats. Compound 6a was found to be active in both assays. This compound could lead to a better understanding of how a bitopic D3 dopamine receptor selective ligand might lead to the development of pharmacotherapeutics for the treatment of levodopa-induced dyskinesia (LID) in patients with Parkinson’s disease.

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11

Wu, Shao-Hsuan, and Jun-Hui Huang. "Two mixed-ligand coordination polymers based on 2,5-thiophenedicarboxylic acid and flexible N-donor ligands: the protective effect on periodontitis via reducing the release of IL-1β and TNF-α." Open Chemistry 18, no. 1 (April 21, 2020): 391–98. http://dx.doi.org/10.1515/chem-2020-0081.

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AbstractTwo novel mixed-ligand coordination polymers, {[Co(tdc)(btrp)]·0.67DMF}n (1) and {[Zn2(bimb)2(tdc)2]·2H2O}n (2) involving 2,5-thiophenedicarboxylate (H2tdc), and bitopic flexible N-donor ligands, 1,3-bis(1,2,4-triazol-1-yl)propane (btrp) and 1,4-bis((1H-benzo[d]imidazol-1-yl)methyl)benzene (bimb), have been synthesized by the hydrothermal method and characterized via IR, elemental analysis, thermal analysis, and powder X-ray diffraction. The biological functional studies were performed; the treatment activity of the compounds on periodontitis and the specific mechanism was explored. First, the real-time RT-PCR was carried out to determine the inflammatory genes nf-κb and p53 relative expression in periodontal mucosal cells after treating with compounds 1 and 2. Then, the level of the inflammatory cytokine in the gingival crevicular fluid after treating with compounds was also determined by the ELISA detection kit.

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12

Meijer, Femke A., Guido J. M. Oerlemans, and Luc Brunsveld. "Orthosteric and Allosteric Dual Targeting of the Nuclear Receptor RORγt with a Bitopic Ligand." ACS Chemical Biology 16, no. 3 (February 17, 2021): 510–19. http://dx.doi.org/10.1021/acschembio.0c00941.

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13

Domasevitch, Konstantin V. "Cobalt(II) chloride complexes with 1,1′-dimethyl-4,4′-bipyrazole featuring first- and second-sphere coordination of the ligand." Acta Crystallographica Section C Structural Chemistry 70, no. 3 (February 8, 2014): 272–76. http://dx.doi.org/10.1107/s2053229614002046.

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Incatena-poly[[dichloridocobalt(II)]-μ-(1,1′-dimethyl-4,4′-bipyrazole-κ2N2:N2′)], [CoCl2(C8H10N4)]n, (1), two independent bipyrazole ligands (Me2bpz) are situated across centres of inversion and in tetraaquabis(1,1′-dimethyl-4,4′-bipyrazole-κN2)cobalt(II) dichloride–1,1′-dimethyl-4,4′-bipyrazole–water (1/2/2), [Co(C8H10N4)2(H2O)4]Cl2·2C8H10N4·2H2O, (2), the Co2+cation lies on an inversion centre and two noncoordinated Me2bpz molecules are also situated across centres of inversion. The compounds are the first complexes involvingN,N′-disubstituted 4,4′-bipyrazole tectons. They reveal a relatively poor coordination ability of the ligand, resulting in a Co–pyrazole coordination ratio of only 1:2. Compound (1) adopts a zigzag chain structure with bitopic Me2bpz links between tetrahedral CoIIions. Interchain interactions occur by means of very weak C—H...Cl hydrogen bonding. Complex (2) comprises discrete octahedraltrans-[Co(Me2bpz)2(H2O)4]2+cations formed by monodentate Me2bpz ligands. Two equivalents of additional noncoordinated Me2bpz tectons are important as `second-sphere ligands' connecting the cations by means of relatively strong O—H...N hydrogen bonding with generation of doubly interpenetratedpcu(α-Po) frameworks. Noncoordinated chloride anions and solvent water molecules afford hydrogen-bonded [(Cl−)2(H2O)2] rhombs, which establish topological links between the above frameworks, producing a rare eight-coordinated uninodal net of {424.5.63} (ilc) topology.

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14

Rossino, Giacomo, Marta Rui, Pasquale Linciano, Daniela Rossi, Massimo Boiocchi, Marco Peviani, Elena Poggio, et al. "Bitopic Sigma 1 Receptor Modulators to Shed Light on Molecular Mechanisms Underpinning Ligand Binding and Receptor Oligomerization." Journal of Medicinal Chemistry 64, no. 20 (October 8, 2021): 14997–5016. http://dx.doi.org/10.1021/acs.jmedchem.1c00886.

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15

Reger, Daniel L., Kenneth J. Brown, James R. Gardinier, and Mark D. Smith. "Syntheses and structural characterizations of rhenium carbonyl complexes of a bitopic ferrocene-linked bis(pyrazolyl)methane ligand." Journal of Organometallic Chemistry 690, no. 8 (April 2005): 1889–900. http://dx.doi.org/10.1016/j.jorganchem.2004.10.048.

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16

Quadros, Helenita C., Aysun Çapcı, Lars Herrmann, Sarah D’Alessandro, Diana Fontinha, Raquel Azevedo, Wilmer Villarreal, et al. "Studies of Potency and Efficacy of an Optimized Artemisinin-Quinoline Hybrid against Multiple Stages of the Plasmodium Life Cycle." Pharmaceuticals 14, no. 11 (November 6, 2021): 1129. http://dx.doi.org/10.3390/ph14111129.

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A recently developed artemisinin-quinoline hybrid, named 163A, has been shown to display potent activity against the asexual blood stage of Plasmodium, the malaria parasite. In this study, we determined its in vitro cytotoxicity to mammalian cells, its potency to suppress P. berghei hepatic infection and to decrease the viability of P. falciparum gametocytes, in addition to determining whether the drug exhibits efficacy of a P. berghei infection in mice. This hybrid compound has a low level of cytotoxicity to mammalian cells and, conversely, a high level of selectivity. It is potent in the prevention of hepatic stage development as well as in killing gametocytes, denoting a potential blockage of malaria transmission. The hybrid presents a potent inhibitory activity for beta-hematin crystal formation, in which subsequent assays revealed that its endoperoxide component undergoes bioactivation by reductive reaction with ferrous heme towards the formation of heme-drug adducts; in parallel, the 7-chloroquinoline component has binding affinity for ferric hemin. Both structural components of the hybrid co-operate to enhance the inhibition of beta-hematin, and this bitopic ligand property is essential for arresting the growth of asexual blood parasites. We demonstrated the in vivo efficacy of the hybrid as an erythrocytic schizonticide agent in comparison to a chloroquine/artemisinin combination therapy. Collectively, the findings suggest that the bitopic property of the hybrid is highly operative on heme detoxification suppression, and this provides compelling evidence for explaining the action of the hybrid on the asexual blood stage. For sporozoite and gametocyte stages, the hybrid conserves the potency typically observed for endoperoxide drugs, and this is possibly achieved due to the redox chemistry of endoperoxide components with ferrous heme.

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17

Reger, Daniel L., Kenneth J. Brown, James R. Gardinier, and Mark D. Smith. "Synthesis and Structural Characterization of a Bitopic Ferrocenyl-Linked Bis(pyrazolyl)methane Ligand and Its Silver(I) Coordination Polymers." Organometallics 22, no. 24 (November 2003): 4973–83. http://dx.doi.org/10.1021/om0305216.

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18

Domasevitch, Konstantin V., Julia A. Rusanova, Ilya A. Gural'skiy, and Pavlo V. Solntsev. "Cadmium(II) chloride, bromide and iodide complexes with 4,4′-bipyridazine: when are diazine and halide bridges (in)compatible?" Acta Crystallographica Section C Crystal Structure Communications 68, no. 11 (October 1, 2012): m295—m299. http://dx.doi.org/10.1107/s0108270112038048.

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In poly[di-μ-chlorido-μ-(4,4′-bipyridazine)-κ2N1:N1′-cadmium(II)], [CdCl2(C8H6N4)]n, (I), and its isomorphous bromide analogue, [CdBr2(C8H6N4)]n, (II), the halide atom lies on a mirror plane and the CdIIion resides at the intersection of two perpendicular mirror planes withm2msite symmetry. The pyridazine rings of the ligand lie in a mirror plane and are related to each other by a second mirror plane perpendicular to the first. The compounds adopt the characteristic structure of the [MIIX2(bipy)] type (bipy is bipyridine) based on crosslinking of [Cd(μ-X)2]nchains [Cd—Cl = 2.5955 (9) and 2.6688 (9) Å; Cd—Br = 2.7089 (4) and 2.8041 (3) Å] by bitopic rod-like organic ligands [Cd—N = 2.368 (3)–2.380 (3) Å]. This feature is discussed in terms of supramolecular stabilization, implying that the periodicity of the inorganic chain [Cd...Cd = 3.7802 (4) Å in (I) and 3.9432 (3) Å in (II)] is favourable for extensive parallel π–π stacking of monodentate pyridazine rings, with centroid–centroid distances of 3.7751 (4) Å in (I) and 3.9359 (4) Å in (II). This is not the case for the longer iodide bridges, which cannot stabilize such a pattern. In poly[tetra-μ-iodido-μ4-(4,4′-bipyridazine)-κ4N1:N2:N1′:N2′-dicadmium(II)], [Cd2I4(C8H6N4)]n, (III), the ligands are situated across a centre of inversion; they are tetradentate [Cd—N = 2.488 (2) and 2.516 (2) Å] and link successive [Cd(μ-I)2]nchains [Cd—I = 2.8816 (3)–3.0069 (4) Å] into corrugated layers.

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19

Sinharoy, P., A. K. Singha Deb, Sk M. Ali, J. N. Sharma, and C. P. Kaushik. "Ligand architectural effect on coordination, bonding, interaction, and selectivity of Am(iii) and Ln(iii) ions with bitopic ligands: synthesis, solvent extraction, and DFT studies." Physical Chemistry Chemical Physics 22, no. 27 (2020): 15448–62. http://dx.doi.org/10.1039/d0cp01615b.

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20

Mistry, Shailesh N., Jeremy Shonberg, Christopher J. Draper-Joyce, Carmen Klein Herenbrink, Mayako Michino, Lei Shi, Arthur Christopoulos, Ben Capuano, Peter J. Scammells, and J. Robert Lane. "Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand." Journal of Medicinal Chemistry 58, no. 17 (August 28, 2015): 6819–43. http://dx.doi.org/10.1021/acs.jmedchem.5b00585.

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21

Reger, Daniel L., Radu F. Semeniuc, Vitaly Rassolov, and Mark D. Smith. "Supramolecular Structural Variations with Changes in Anion and Solvent in Silver(I) Complexes of a Semirigid, Bitopic Tris(pyrazolyl)methane Ligand." Inorganic Chemistry 43, no. 2 (January 2004): 537–54. http://dx.doi.org/10.1021/ic035207i.

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22

Reger, Daniel L., Kenneth J. Brown, James R. Gardinier, and Mark D. Smith. "Synthesis and structural characterization of the bitopic ferrocene-based tris(pyrazolyl)methane ligand Fe[C5H4CH2OCH2C(pz)3]2 (pz = pyrazolyl ring)." Journal of Chemical Crystallography 35, no. 3 (March 2005): 217–25. http://dx.doi.org/10.1007/s10870-005-2960-7.

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23

Cooper, Samantha L., Julie March, Andrea R. Sabbatini, Stephen J. Hill, Manuela Jörg, Peter J. Scammells, and Jeanette Woolard. "The effect of two selective A 1 ‐receptor agonists and the bitopic ligand VCP746 on heart rate and regional vascular conductance in conscious rats." British Journal of Pharmacology 177, no. 2 (January 2020): 346–59. http://dx.doi.org/10.1111/bph.14870.

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24

Root-Bernstein, Robert. "Biased, Bitopic, Opioid–Adrenergic Tethered Compounds May Improve Specificity, Lower Dosage and Enhance Agonist or Antagonist Function with Reduced Risk of Tolerance and Addiction." Pharmaceuticals 15, no. 2 (February 10, 2022): 214. http://dx.doi.org/10.3390/ph15020214.

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This paper proposes the design of combination opioid–adrenergic tethered compounds to enhance efficacy and specificity, lower dosage, increase duration of activity, decrease side effects, and reduce risk of developing tolerance and/or addiction. Combinations of adrenergic and opioid drugs are sometimes used to improve analgesia, decrease opioid doses required to achieve analgesia, and to prolong the duration of analgesia. Recent mechanistic research suggests that these enhanced functions result from an allosteric adrenergic binding site on opioid receptors and, conversely, an allosteric opioid binding site on adrenergic receptors. Dual occupancy of the receptors maintains the receptors in their high affinity, most active states; drops the concentration of ligand required for full activity; and prevents downregulation and internalization of the receptors, thus inhibiting tolerance to the drugs. Activation of both opioid and adrenergic receptors also enhances heterodimerization of the receptors, additionally improving each drug’s efficacy. Tethering adrenergic drugs to opioids could produce new drug candidates with highly desirable features. Constraints—such as the locations of the opioid binding sites on adrenergic receptors and adrenergic binding sites on opioid receptors, length of tethers that must govern the design of such novel compounds, and types of tethers—are described and examples of possible structures provided.

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25

Białońska, Agata, Robert Bronisz, Joachim Kusz, and Maciej Zubko. "Two-Step Spin Transition in an Iron(II) Coordination Network Based on Flexible Bitopic Ligand 1-(Tetrazol-1-yl)-3-(1,2,3-triazol-1-yl)propane." European Journal of Inorganic Chemistry 2013, no. 5-6 (November 9, 2012): 884–93. http://dx.doi.org/10.1002/ejic.201200960.

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26

Kusz, Joachim, Maria Ksiazek, Robert Bronisz, and Marek Weselski. "Two-step spin transition and superstructure in an iron(II) coordination network based on flexible bitopic ligand 1-(tetrazol-1- yl)-3-(1,2,3-triazol-1-yl)propane." Acta Crystallographica Section A Foundations and Advances 71, a1 (August 23, 2015): s432. http://dx.doi.org/10.1107/s2053273315093638.

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27

Zięba, Agata, Justyna Żuk, Damian Bartuzi, Dariusz Matosiuk, Antti Poso, and Agnieszka A. Kaczor. "The Universal 3D QSAR Model for Dopamine D2 Receptor Antagonists." International Journal of Molecular Sciences 20, no. 18 (September 14, 2019): 4555. http://dx.doi.org/10.3390/ijms20184555.

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In order to search for novel antipsychotics acting through the D2 receptor, it is necessary to know the structure–activity relationships for dopamine D2 receptor antagonists. In this context, we constructed the universal three-dimensional quantitative structure–activity relationship (3D- QSAR) model for competitive dopamine D2 receptor antagonists. We took 176 compounds from chemically different groups characterized by the half maximal inhibitory concentration (IC50)from the CHEMBL database and docked them to the X-ray structure of the human D2 receptor in the inactive state. Selected docking poses were applied for Comparative Molecular Field Analysis (CoMFA) alignment. The obtained CoMFA model is characterized by a cross-validated coefficient Q2 of 0.76 with an optimal component of 5, R2 of 0.92, and an F value of 338.9. The steric and electrostatic field contributions are 67.4% and 32.6%, respectively. The statistics obtained prove that the CoMFA model is significant. Next, the IC50 of the 16 compounds from the test set was predicted with R2 of 0.95. Finally, a progressive scrambling test was carried out for additional validation. The CoMFA fields were mapped onto the dopamine D2 receptor binding site, which enabled a discussion of the structure–activity relationship based on ligand–receptor interactions. In particular, it was found that one of the desired steric interactions covers the area of a putative common allosteric pocket suggested for some other G protein-coupled receptors (GPCRs), which would suggest that some of the known dopamine receptor antagonists are bitopic in their essence. The CoMFA model can be applied to predict the potential activity of novel dopamine D2 receptor antagonists.

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Reger, Daniel L., Christine A. Little, Radu F. Semeniuc, and Mark D. Smith. "Synthesis and structural characterization of a mixed-ligand diiron(II) complex formed by a linked bitopic tris(pyrazolyl)methane ligand: {HC(3,5-Me2pz)3Fe[μ-p-C6H4(CH2OCH2C(pz)3)2]Fe(3,5-Me2pz)3CH}(BF4)4 (pz=pyrazolyl ring)." Inorganica Chimica Acta 362, no. 1 (January 2009): 303–6. http://dx.doi.org/10.1016/j.ica.2008.03.120.

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29

Stank, Lars, Annika Frank, Stefanie Hagenow, and Holger Stark. "Talipexole variations as novel bitopic dopamine D2 and D3 receptor ligands." MedChemComm 10, no. 11 (2019): 1926–29. http://dx.doi.org/10.1039/c9md00379g.

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30

Liu, Jiquan, Yeping Xu, Pedro B. Groszewicz, Martin Brodrecht, Claudia Fasel, Kathrin Hofmann, Xijuan Tan, Torsten Gutmann, and Gerd Buntkowsky. "Novel dirhodium coordination polymers: the impact of side chains on cyclopropanation." Catalysis Science & Technology 8, no. 20 (2018): 5190–200. http://dx.doi.org/10.1039/c8cy01493k.

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Jakubik, Jan, and Esam E. El-Fakahany. "Current Advances in Allosteric Modulation of Muscarinic Receptors." Biomolecules 10, no. 2 (February 18, 2020): 325. http://dx.doi.org/10.3390/biom10020325.

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Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency, and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated G-protein-coupled receptors. They are a potential therapeutic target for the treatment of psychiatric, neurologic, and internal diseases like schizophrenia, Alzheimer’s disease, Huntington disease, type 2 diabetes, or chronic pulmonary obstruction. Here, we reviewed the progress made during the last decade in our understanding of their mechanisms of binding, allosteric modulation, and in vivo actions in order to understand the translational impact of studying this important class of pharmacological agents. We overviewed newly developed allosteric modulators of muscarinic receptors as well as new spin-off ideas like bitopic ligands combining allosteric and orthosteric moieties and photo-switchable ligands based on bitopic agents.

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32

Potapov, Andrei S., Evgenia A. Nudnova, Vladimir D. Ogorodnikov, Tatiana V. Petrenko, and Andrei I. Khlebnikov. "Synthesis of New Bitopic Tetra(pyrazolyl)-Ligands with Neopentane and O-Xylene Backbones." Scientific World Journal 2012 (2012): 1–5. http://dx.doi.org/10.1100/2012/798271.

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Several new bitopic pyrazole-containing ligands were prepared from the corresponding pyrazoles and tetrahalogen or tetratosyloxy derivatives of o-xylene and neopentane in a superbasic medium (KOH-DMSO).

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Valant, C., P. M. Sexton, and A. Christopoulos. "Orthosteric/Allosteric Bitopic Ligands: Going Hybrid at GPCRs." Molecular Interventions 9, no. 3 (June 1, 2009): 125–35. http://dx.doi.org/10.1124/mi.9.3.6.

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34

Shonberg, Jeremy, Christopher Draper-Joyce, Shailesh N. Mistry, Arthur Christopoulos, Peter J. Scammells, J. Robert Lane, and Ben Capuano. "Structure–Activity Study of N-((trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a Bitopic Ligand That Acts as a Negative Allosteric Modulator of the Dopamine D2 Receptor." Journal of Medicinal Chemistry 58, no. 13 (June 24, 2015): 5287–307. http://dx.doi.org/10.1021/acs.jmedchem.5b00581.

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35

Jo, Euijung, Barun Bhhatarai, Emanuela Repetto, Miguel Guerrero, Sean Riley, Steven J. Brown, Yasushi Kohno, Edward Roberts, Stephan C. Schürer, and Hugh Rosen. "Novel Selective Allosteric and Bitopic Ligands for the S1P3Receptor." ACS Chemical Biology 7, no. 12 (September 14, 2012): 1975–83. http://dx.doi.org/10.1021/cb300392z.

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Koepf, Matthieu, Jesse J. Bergkamp, Anne-Lucie Teillout, Manuel J. Llansola-Portoles, Gerdenis Kodis, Ana L. Moore, Devens Gust, and Thomas A. Moore. "Design of porphyrin-based ligands for the assembly of [d-block metal : calcium] bimetallic centers." Dalton Transactions 46, no. 13 (2017): 4199–208. http://dx.doi.org/10.1039/c6dt04647a.

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37

Lane, J. Robert, Patrick M. Sexton, and Arthur Christopoulos. "Bridging the gap: bitopic ligands of G-protein-coupled receptors." Trends in Pharmacological Sciences 34, no. 1 (January 2013): 59–66. http://dx.doi.org/10.1016/j.tips.2012.10.003.

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38

Marie, Cécile, Manuel Miguirditchian, Denis Guillaneux, Julia Bisson, Muriel Pipelier, and Didier Dubreuil. "New Bitopic Ligands for the Group Actinide Separation by Solvent Extraction." Solvent Extraction and Ion Exchange 29, no. 2 (March 18, 2011): 292–315. http://dx.doi.org/10.1080/07366299.2011.556923.

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39

Morales, Paula, Gemma Navarro, Marc Gómez‐Autet, Laura Redondo, Javier Fernández‐Ruiz, Laura Pérez‐Benito, Arnau Cordomí, Leonardo Pardo, Rafael Franco, and Nadine Jagerovic. "Discovery of Homobivalent Bitopic Ligands of the Cannabinoid CB 2 Receptor**." Chemistry – A European Journal 26, no. 68 (November 9, 2020): 15839–42. http://dx.doi.org/10.1002/chem.202003389.

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40

Bieller, Susanne, Fan Zhang, Michael Bolte, Jan W. Bats, Hans-Wolfram Lerner, and Matthias Wagner. "Bitopic Bis- and Tris(1-pyrazolyl)borate Ligands: Syntheses and Structural Characterization." Organometallics 23, no. 9 (April 2004): 2107–13. http://dx.doi.org/10.1021/om049954e.

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41

Reger, Daniel L., Russell P. Watson, Mark D. Smith, and Perry J. Pellechia. "Metallacyclic Zinc Complexes of Alkylidene-Linked Bitopic Bis(pyrazolyl)methane Ligands: Unusual Exocyclic Bridging Fluoride Ligands." Crystal Growth & Design 7, no. 6 (June 2007): 1163–70. http://dx.doi.org/10.1021/cg070078s.

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42

Reinecke, Bethany A., Huiqun Wang, and Yan Zhang. "Recent Advances in the Drug Discovery and Development of Dualsteric/ Bitopic Activators of G Protein-Coupled Receptors." Current Topics in Medicinal Chemistry 19, no. 26 (December 10, 2019): 2378–92. http://dx.doi.org/10.2174/1568026619666191009164609.

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G protein-coupled receptors (GPCRs) represent the largest family of proteins targeted by drug design and discovery efforts. Of these efforts, the development of GPCR agonists is highly desirable, due to their therapeutic robust utility in treating diseases caused by deficient receptor signaling. One of the challenges in designing potent and selective GPCR agonists lies in the inability to achieve combined high binding affinity and subtype selectivity, due to the high homology between orthosteric sites among GPCR subtypes. To combat this difficulty, researchers have begun to explore the utility of targeting topographically distinct and less conserved binding sites, namely “allosteric” sites. Pursuing these sites offers the benefit of achieving high subtype selectivity, however, it also can result in a decreased binding affinity and potency as compared to orthosteric agonists. Therefore, bitopic ligands comprised of an orthosteric agonist and an allosteric modulator connected by a spacer and allowing binding with both the orthosteric and allosteric sites within one receptor, have been developed. It may combine the high subtype selectivity of an allosteric modulator with the high binding affinity of an orthosteric agonist and provides desired advantages over orthosteric agonists or allosteric modulators alone. Herein, we review the recent advances in the development of bitopic agonists/activators for various GPCR targets and their novel therapeutic potentials.

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Tahtaoui, Chouaib, Isabelle Parrot, Philippe Klotz, Fabrice Guillier, Jean-Luc Galzi, Marcel Hibert, and Brigitte Ilien. "Fluorescent Pirenzepine Derivatives as Potential Bitopic Ligands of the Human M1 Muscarinic Receptor." Journal of Medicinal Chemistry 47, no. 17 (August 2004): 4300–4315. http://dx.doi.org/10.1021/jm040800a.

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Volpato, Daniela, Michael Kauk, Regina Messerer, Marcel Bermudez, Gerhard Wolber, Andreas Bock, Carsten Hoffmann, and Ulrike Holzgrabe. "The Role of Orthosteric Building Blocks of Bitopic Ligands for Muscarinic M1 Receptors." ACS Omega 5, no. 49 (December 1, 2020): 31706–15. http://dx.doi.org/10.1021/acsomega.0c04220.

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Valant, Celine, J. Robert Lane, Patrick M. Sexton, and Arthur Christopoulos. "The Best of Both Worlds? Bitopic Orthosteric/Allosteric Ligands of G Protein–Coupled Receptors." Annual Review of Pharmacology and Toxicology 52, no. 1 (February 10, 2012): 153–78. http://dx.doi.org/10.1146/annurev-pharmtox-010611-134514.

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Chiu, Pei Ling, Chih Yuan Chen, Chun-Chin Lee, Meng-Hua Hsieh, Chuan-Hung Chuang, and Hon Man Lee. "Structural Variations in Novel Silver(I) Complexes with Bitopic Pyrazole/N-Heterocyclic Carbene Ligands." Inorganic Chemistry 45, no. 6 (March 2006): 2520–30. http://dx.doi.org/10.1021/ic051840n.

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Faouzi, Abdelfattah, Saheem Zaidi, Tao Che, Chad Kormos, Tiffany Zhang, Manish Madasu, Shainnel Eans, et al. "Design of first in class bitopic ligands targeting the sodium binding pocket in opioid receptors." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.02437.

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48

Daval, Sandrine B., Esther Kellenberger, Dominique Bonnet, Valérie Utard, Jean-Luc Galzi, and Brigitte Ilien. "Exploration of the Orthosteric/Allosteric Interface in Human M1 Muscarinic Receptors by Bitopic Fluorescent Ligands." Molecular Pharmacology 84, no. 1 (April 19, 2013): 71–85. http://dx.doi.org/10.1124/mol.113.085670.

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Fronik, Philipp, Birgit I. Gaiser, and Daniel Sejer Pedersen. "Bitopic Ligands and Metastable Binding Sites: Opportunities for G Protein-Coupled Receptor (GPCR) Medicinal Chemistry." Journal of Medicinal Chemistry 60, no. 10 (February 15, 2017): 4126–34. http://dx.doi.org/10.1021/acs.jmedchem.6b01601.

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50

Davie, Briana J., Arthur Christopoulos, and Peter J. Scammells. "Development of M1mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits." ACS Chemical Neuroscience 4, no. 7 (May 23, 2013): 1026–48. http://dx.doi.org/10.1021/cn400086m.

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