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Kim, Ho Young ; Lee, Ji Youn ; Hsieh, Chia-Ju , et al. Int. J. Mol. Sci.,2023,24(1):432. DOI: 10.3390/ijms24010432 PubMed ID: 36613875
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Abstract: Previous studies have confirmed that the binding of D3?receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D3?receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D3?receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D3?receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D3?receptor affinities (Ki = 0.8–13.2 nM) with subtype selectivity to the D2?receptor ranging from 22- to 180-fold. The β-arrestin recruitment assay revealed that?21c?with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC50?= 1.3 nM). Computational studies demonstrated that the high potency of?21c?and its analogs was the result of interactions with the secondary binding site of the D3?receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT3?receptors and TSPO. The results of this study revealed that a new class of selective D3?receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.
Keywords: D3 receptor antagonists ; metoclopramide ; bitopic ligand ; β-arrestin recruitment assay ; computational chemistry
Purchased from AmBeed: 5460-29-7 ; 88-13-1 ; 29886-62-2 ; 64951-08-2 ; 55-22-1 ; 1477-50-5 ; 16136-58-6 ; 62563-07-9 ; 5394-18-3 ; 5003-71-4 ; 29886-64-4 ; 105628-63-5 ; 2243-83-6 ; 459-57-4 ; 486-74-8 ; 87227-41-6 ; 105299-45-4 ; 5458-14-0 ; 72517-23-8 ; 38942-51-7 ...More
CAS No. : | 5460-29-7 | MDL No. : | MFCD00005904 |
Formula : | C11H10BrNO2 | Boiling Point : | No data available |
Linear Structure Formula : | C6H4(CO)2N(CH2)3Br | InChI Key : | VKJCJJYNVIYVQR-UHFFFAOYSA-N |
M.W : | 268.11 | Pubchem ID : | 21611 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | |
Hazard Statements: | H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; water; | PREPARATION 4 2-[3-[4-[2-(Dimethylamino)ethyl]phenoxy]propyl]-1H-isoindole-1,3-(2H)-dione A mixture of 4-[2-(dimethylamino)ethyl]phenol (4.13 g) and sodium hydride (0.67 g) in dimethylformamide was stirred at room temperature for 24 h. N-(3-Bromopropyl) phthalimide (6.7 g) was added at 0 and stirring was continued for 24 h. The solution was treated with water and extracted with ether. Evaporation of the solvent gave the title compound as a white solid which was recrystallized from light petroleum (b.p. 60-80) 2.3 g) m.p. 81-82. TLC silica; ethyl acetate:water:isopropanol:0.88 ammonia 25:8:15:2; Rf 0.45. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine hydrate; In methanol; 5,5-dimethyl-1,3-cyclohexadiene; ethanol; ethyl acetate; | 3-[(3-Aminopropyl)amino]-N,N-dimethylbenzamide A mixture of <strong>[33322-60-0]3-amino-N,N-dimethylbenzamide</strong> (15.4 g) and N-(3-bromopropyl)phthalimide (12 g) in dry xylene was heated under reflux during 12 hr. The precipitate that formed was dissolved in methanol and ethyl acetate added. The mixture was washed with water and the organic phase was evaporated to leave a crude oil (15 g) which was used without further purification. The oil and hydrazine hydrate (5.55 g) were heated under reflux in ethanol for 2 hr and then cooled to 25. A solid precipitate that formed was removed by filtration and the filtrate concentrated in vacuo to give the title compound (2.2 g) b.p. 170-5, (0.01 mm). TLC silica; methanol:ammonia (80:1) Rf 0.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 6h;Inert atmosphere; | General procerure: To a suspension of mercaptan substituent heterocyclic in DMF, one equivalent of N-(3-bromopropyl) phthalimide and K2CO3 (1 equivalent) were added. The reaction was stirred for 6 h at 90 C before cooled to room temperature. After evaporation of the DMF under vacuum, the residue was diluted with methylene chloride, washed with water and brine, and dried over MgSO4. After evaporation of the solution, the crude products were purified by column chromatography eluting with 2.5:1 petroleum ether/acetone to afford the desired products as yellow or white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With potassium carbonate; In acetonitrile; at 80℃; for 48.0h; | A mixture of compound 4 (1 .3 g; 2.9 mmol), N-(3-bromopropyl) phtalimide (1.56 g; 5.8 mmol) and K2C03 (0.805 g; 5.8 mmol) in CH3CN (100 mL) was stirred at 80C for 48 hours. The reaction mixture was cooled to room temperature, poured out into ice water and EtOAc was added. The organic layer was separated, washed with brine, dried (MgS04), filtered and the solvent was evaporated until dryness. The residue (0.566 g) was purified by chromatography over silica gel (SiOH, 15-40mueta-iota, 50g; mobile phase 0.1 % NH4OH, 96% DCM, 4% MeOH ). The product fractions were collected and the solvent was evaporated to give 1 .26 g (34%) of intermediate 87. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 60.0℃; for 3.0h; | 4,6-dichloro-lH-indole (1 eq) was dissolved in DMF, K2COj (3eq) and 2-(3~ bromopropyl)isoindoline-l,3-dione (1.1 eq) was added and the mixture stirred at 60 C for 3 h. Solvent was removed and extracted with DCM. The organic extract was washed with water, brine and dried over Ma2S04. The residue was purified via flash chromatography on silica gel to obtain 2-(3-(4,6-dich3oro- lH-indoi-l-yr)propyi)isoindoline- .l,3-dione. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | NaH (60% in mineral oil) (3.0 g; 75.2 mmol) was suspended in a mixture of dry THFDMF(1:1; 200 mL), Keto-ester 15 (10.0 g; 34.2 mmol) dissolved in dry THF was addeddropwise at 0 C, the resulting solution allowed to stir for 10 min to complete deprotonation.Then bromopropyl-pthalimide 16 (11.2 g; 41.02 mmol) in dry THF was added slowly at 0 C.Then the reaction mixture was fitted with a refluxing condenser and heated at 65 C forovernight. The reaction completion was monitored by TLC and cooled to room temp and thenthe pH of the reaction mixture was adjusted to neutral with 1.0M aq. HCl. The layers wereseparated and aq. layer was extracted with EtOAc, combined organic layer was washed withwater, brine solution dried over anhydrous Na2SO4. After concentration the crude residue wasthen purified by column chromatography using 10-15% EtOAc in pet-ether as a gradient togive pure pthalimide derivative (17) 9.5 g (64% yield). 1H NMR (400 MHz, CDCl3) delta 7.84 -7.79 (m, 2H), 7.72 - 7.67 (m, 2H), 7.33 - 7.22 (m, 5H), 3.71 (s, 3H), 3.65 (q, J = 6.8 Hz, 2H),3.55 (d, J = 7.8 Hz, 2H), 3.33 (d, J = 11.1 Hz, 1H), 2.91 (d, J = 49.9 Hz, 2H), 2.37 (d, J =14.5 Hz, 2H), 2.21 (d, J = 11.2 Hz, 1H), 1.89 - 1.65 (m, 2H), 1.49 (dtd, J = 17.4, 13.0, 5.1 Hz, 2H).; 13C NMR (101 MHz, cdcl3) delta 206.0, 168.5, 134.1, 132.3, 129.0, 128.5, 127.6,123.4, 61.9, 61.1, 60.6, 53.8, 52.5, 40.6, 38.2, 29.4, 24.1, 21.3, 14.4.; HPLC-MS (ESI) m/zcalcd. for C25H27N2O5 [M+H]+ = 435.18. Found: 435.24.TLC stain: UV, I2, KMnO4Rf: 0.3 (30% EtOAc in pet-ether) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | To a solution of compound 1 (6.0 g, 9.8 mmol) in DMF (78 mL), NaH (0.47 g, 19.6 mmol) was added.The mixture was stirred for 30 min at ambient temperature, then N-(3-bromopropyl)-phthalimide(3.2 g, 11.8 mmol) was added in an ice-water bath. The mixture was stirred for 30 min in the ice-waterbath under N2. The temperature gradually raised to room temperature under N2 and the mixture wasstirred 6 h until the reaction completed. The reaction mixture was diluted with water and extractedwith DCM (2 80 mL). The combined organic phase was washed with water and brine, dried overanhydrous Na2SO4 and filtered, followed by solvent removal. The residue was purified over by flashchromatography over silica gel using a gradient of DCM/MeOH as the eluent to givecompound 6(3.90 g). 50% yield; light yellow solid; mp: 190-192 C. 1H-NMR (CDCl3) delta 7.85-7.80 (m, 2H), 7.73-7.68(m, 2H), 7.38 (dd, J = 8.2, 2.1 Hz, 1H), 7.14 (dd, J = 8.2, 2.5 Hz, 1H), 6.90-6.84 (m, 2H), 6.82 (dd, J = 8.3,2.5 Hz, 1H), 6.54 (s, 1H), 6.50 (d, J = 1.2 Hz, 1H), 6.33 (dd, J = 8.3, 2.1 Hz, 1H), 6.29 (s, 1H), 5.98 (s, 1H),3.93 (s, 3H), 3.88-3.83 (m, 1H), 3.75-3.70 (m, 4H), 3.61-3.41 (m, 6H), 3.38 (s, 3H), 3.35-3.28 (m, 1H),2.96-2.87 (m, 4H), 2.81-2.67 (m, 4H), 2.54-2.47 (m, 1H), 2.45 (s, 3H), 2.32 (s, 3H), 1.66-1.57 (m, 1H),1.50-1.41 (m, 1H); 13C-NMR (CDCl3) delta 168.2 (2), 153.7, 151.4, 149.4, 148.7, 148.2, 147.0, 143.7, 136.5,134.9, 134.5, 133.9 (2), 132.6, 132.1 (2), 130.3, 128.2, 127.8, 123.1 (2), 122.8, 122.5, 122.0 (2), 120.0 (2), 115.9,112.8, 111.4, 105.8, 70.2, 64.0, 61.4, 56.1, 55.8, 55.7, 45.2, 44.2, 42.3, 42.1, 41.7, 39.7, 35.3, 28.4, 24.3, 22.1;HRMS: calcd for C48H50N3O8 [M + H]+: 796.3592, found: 796.3604. |
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