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.
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With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 0.75h;
To a solution of 500 mg (2.78 mmol) of 3-(trifluoromethyl)-lNo.-pyrazole-5-carboxylicacid, 682 mg (3.05 mmol) of 3-brornopropylamine hydrobromide, and 1.4 mL (1.04 g, 8.04 mmol) ofAr,W-diisopropylethylamine in 20 mL of dichloromethane were added 1.2 g (3.06 mmol) of O-(7-azabenzotriazol-l-yl)-N,]V,Af',7V'-tetramethyluromumhexafluorophosphate (HATU) and 459 mg (3.38mmol) of l-hydroxy-7-azabenzotriazole (HOAT). After being stirred at room temperature for 45 min, thereaction mixture was partitioned between dichloromethane and saturated sodium carbonate aqueoussolution. The organic phase was washed with 5% aqueous citric acid solution, then dried over sodiumsulfate, and concentrated. The residue was leached with dichloromethane containing a little methanol.Concentration of the organic extract yielded the title compound. LC-MS 300, 302 (M+l).
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