Du et al R2 R2 11a-11 Scheme 2: Syntheses of compounds 11a-q. Reagents and conditions: (a) chloroacetylchloride, TEA, DCM;(b)Boc-piperazine, K2CO3, CH3CN; (c) TFADCM;(d) 3a-3d, 6b, K2CO3, CH3CN Acknowledgment 7. Banala A K, Levy B.A. Khatri S.S., Furman C A, Roof R.A., Mishra Y, Griffin S.A., Sibley D R, Luedtke R.R This work was supported by the National Natural Science Newman A H.(2011)N-(3-fluoro-4-(4-(2-methoxy or Foundation of China (No. 81172919, 81130023 2, 3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamid 0825042)and grants from the National High Technology es as selective dopamine D3 receptor ligands: critical Research and Development Program of China(863 Pro- ole of the carboxamide linker for D3 receptor selectiv gram)(No. 2012AA020301), the State Key Program of ity. J Med Chem; 54: 3581-3594 Basic Research of China grant (2009CB918502, 8. Micheli F, Arista L, Bertani B, Braggio S, Capell 2010cB912601,2009CB522000,and2011CB5C4403) A M, Cremonesi S, Di-Fabio R. et al. (2010) Explora and National Drug Innovative Program(No. 2009ZX0930 tion of the amine terminus in a novel series of 1.2.4- 011). Support from Priority Academic Program Develop triazolo-3-yl-azabicyclo(3. 1.0 hexanes as selective ment of Jiangsu Higher Education Institutes(PAPD)is also d D3 appreciated. Chem:53:7129-7139 9. Micheli F, Arista L, Bonanomi G, Blaney FE, Braggio S, Capelli A M., Checchia A. et al.(2010)1, 2, 4-Triaz References olyl azabicyclo(3.1.0]hexanes: a new series of potent and selective dopamine D(3)receptor antagonists. J 1. Sokoloff P. Giros B. Martres M.P. Bouthenet m.l. Med chem;:53:374391 Schwartz J.C. (1990)Molecular cloning and character- 10. Li B, Li W, Du P, Yu K.Q., Fu W.(2012)Molecular ization of a novel dopamine receptor(D3)as a target Insights into the D1R Agonist and D2R/D3R Antagonist for neuroleptics. Nature 347: 146-151 Effects of the Natural Product (-)-Stepholidine: molec. 2. Richtand N M, Woods S.C., Berger S.P., Strakowski ular Modeling and Dynamics Simulations. J Phys S M.(2001)D3 dopamine receptor, behavioral sensitize Chem B:116:81218130 tion, and psychosis. Neurosci Biobehav Rev: 25: 427-443. 11. Chien E.Y., Liu W, Zhao Q, Katritch V, Han GW 3. Joyce J.N., Millan M.J.(2005)Dopamine D3 receptor Hanson mA. shi L. Newman A.h., Javitch JA antagonists as therapeutic agents. Drug Discov Cherezov V, Stevens R C.(2010) Structure of the Today;:10:917-925 human dopamine d3 receptor in complex with a D2 4. Heidbreder C.(2008) Selective antagonism at dopa- D3 selective antagonist. Science; 330: 1091-1095 mine D3 receptors as a target for drug addiction phar- 12. Bettinetti L, Schlotter K, Hubner H, Gmeiner P herapy: a review of preclinical evidence. CNS (2002) Interactive SAR studies: rational discovery of Neurol Disord Drug Targets; 7: 410-421 super-potent and highly selective dopamine D3 recep 5. Micheli F, Heidbreder C(2013)Dopamine D3 receptor tor antagonists and partial agonists. J Med antagonists: a patent review(2007-2012). Expert Opin Chem;45:45944597 Ther Pat;23:363-381 13. Robarge M.J., Husbands S.M., Kieltyka A, Brodbeck 6. Chen J, Collins G.T., Zhang J, Yang C.Y., Levant B R, Thurkauf A, Newman A H.(2001)Design and syn Woods J, Wang S(2008)Design, synthesis, and eval- thesis of [(2, 3-dichlorophenyl)piperazin-1-ylJalkylifluore- uation of potent and selective ligands for the dopamine nylcarboxamides as novel ligands selective for the 3(D3)receptor with a novel in vivo behavioral profile dopamine D3 receptor subtype. J Med Med chem:51:5905-5908 Chem;44:31753186 Chem Biol Drug Des 2013: 82: 326-335Acknowledgment This work was supported by the National Natural Science Foundation of China (No. 81172919, 81130023, 30825042) and grants from the National High Technology Research and Development Program of China (863 Pro￾gram) (No. 2012AA020301), the State Key Program of Basic Research of China grant (2009CB918502, 2010CB912601, 2009CB522000, and 2011CB5C4403), and National Drug Innovative Program (No. 2009ZX09301- 011). Support from Priority Academic Program Develop￾ment of Jiangsu Higher Education Institutes (PAPD) is also appreciated. References 1. Sokoloff P., Giros B., Martres M.P., Bouthenet M.L., Schwartz J.C. (1990) Molecular cloning and character￾ization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature;347:146–151. 2. Richtand N.M., Woods S.C., Berger S.P., Strakowski S.M. (2001) D3 dopamine receptor, behavioral sensitiza￾tion, and psychosis. Neurosci Biobehav Rev;25:427–443. 3. Joyce J.N., Millan M.J. (2005) Dopamine D3 receptor antagonists as therapeutic agents. Drug Discov Today;10:917–925. 4. Heidbreder C. (2008) Selective antagonism at dopa￾mine D3 receptors as a target for drug addiction phar￾macotherapy: a review of preclinical evidence. CNS Neurol Disord Drug Targets;7:410–421. 5. Micheli F., Heidbreder C. (2013) Dopamine D3 receptor antagonists: a patent review (2007–2012). Expert Opin Ther Pat;23:363–381. 6. Chen J., Collins G.T., Zhang J., Yang C.Y., Levant B., Woods J., Wang S. (2008) Design, synthesis, and eval￾uation of potent and selective ligands for the dopamine 3 (D3) receptor with a novel in vivo behavioral profile. J Med Chem;51:5905–5908. 7. Banala A.K., Levy B.A., Khatri S.S., Furman C.A., Roof R.A., Mishra Y., Griffin S.A., Sibley D.R., Luedtke R.R., Newman A.H. (2011) N-(3-fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamid￾es as selective dopamine D3 receptor ligands: critical role of the carboxamide linker for D3 receptor selectiv￾ity. J Med Chem;54:3581–3594. 8. Micheli F., Arista L., Bertani B., Braggio S., Capelli A.M., Cremonesi S., Di-Fabio R. et al. (2010) Explora￾tion of the amine terminus in a novel series of 1,2,4- triazolo-3-yl-azabicyclo[3.1.0]hexanes as selective dopamine D3 receptor antagonists. J Med Chem;53:7129–7139. 9. Micheli F., Arista L., Bonanomi G., Blaney F.E., Braggio S., Capelli A.M., Checchia A. et al. (2010) 1,2,4-Triaz￾olyl azabicyclo[3.1.0]hexanes: a new series of potent and selective dopamine D(3) receptor antagonists. J Med Chem;53:374–391. 10. Li B., Li W., Du P., Yu K.Q., Fu W. (2012) Molecular Insights into the D1R Agonist and D2R/D3R Antagonist Effects of the Natural Product (
)-Stepholidine: molec￾ular Modeling and Dynamics Simulations. J Phys Chem B;116:8121–8130. 11. Chien E.Y., Liu W., Zhao Q., Katritch V., Han G.W., Hanson M.A., Shi L., Newman A.H., Javitch J.A., Cherezov V., Stevens R.C. (2010) Structure of the human dopamine D3 receptor in complex with a D2/ D3 selective antagonist. Science;330:1091–1095. 12. Bettinetti L., Schlotter K., Hubner H., Gmeiner P. (2002) Interactive SAR studies: rational discovery of super-potent and highly selective dopamine D3 recep￾tor antagonists and partial agonists. J Med Chem;45:4594–4597. 13. Robarge M.J., Husbands S.M., Kieltyka A., Brodbeck R., Thurkauf A., Newman A.H. (2001) Design and syn￾thesis of [(2,3-dichlorophenyl)piperazin-1-yl]alkylfluore￾nylcarboxamides as novel ligands selective for the dopamine D3 receptor subtype. J Med Chem;44:3175–3186. H N R3 a N Cl R3 O b N N R3 BocN O c N N R3 HN O N R3 O N N N H R1 n d 7 8 9 10 11a-11q R2 R2 R2 R2 R2 Scheme 2: Syntheses of compounds 11a–q. Reagents and conditions: (a) chloroacetylchloride, TEA, DCM; (b) Boc-piperazine, K2CO3, CH3CN; (c) TFA/DCM; (d) 3a–3d, 6b, K2CO3, CH3CN. 334 Chem Biol Drug Des 2013; 82: 326–335 Du et al