1784 高等学校化学学报 Vol 32 9]Chien E. Y. T, Liu W, Zhao Q, Katritch V, Han G. W, Hanson M. A, Shi L, Newman A. H, Javitch J. A, Cherezov V. etal. Science[J,2010,330:1091-1095 [10] Leach C. The British Journal of Clinical Psychology/the British Psychological Society[ J]. 1988, 27(P12): 173-174 1] Guener 0., Clement 0., Kurogi Y. Current Medicinal Chemistry[J], 2004, 11(22): 2991--3005 [12] Binkowski T. A, Naghibzadeh S, Liang J. Nucleic Acids Research[J], 2003, 31(13): 3352-3355 [13 Frisch M, Trucks G, Cheeseman J, Scalmani G, Clemente F, Hratchina H, Caricato M, Izmaylov A, Hess J, Adria C,ef aL.. Gaussian 09, Revision Al[CP], Wallingford CT: Gaussian Inc, 200 [14 Rocchia W, Alexow E, Honig B. J. Phys. Chem. B[J]. 2001,105: 6507-6514 [15] BAO Hong-Juan(鲍红娟), TANG Ya-Ling(唐亚林), XU Xiao-Jie(徐筱杰),Ⅺ ANG Jun-Feng(向俊峰), ZHENG Zhi-Hui(郑智 慧).Chem.J. Chinese universities(高等学校化学学报)[门],2010,31(5):938 Discovery of a Novel Dopamine D, Receptor Inhibitor DENG Xin-Xian, SHEN Qing, XU Li-Li, XIONG Zi-Jun ZHAO Wei-Li ZHEN Xue-Chu2 FU Weil (1. Department of Medicinal Chemistry, School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education PLA, Fudan University, Shanghai 201203, China; 2. State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China Abstract Dopamine D, receptor regulates the synthesis and release of dopamine in brain. It is implicated in many neurological processes, including motivation, pleasure, cognitie emory, learning, and fine motor control. It is involved in the pathology of psychotic diseases, such as schizophrenia, Parkinsons disease and drug addiction. It is of great significance to discover novel D, inhibitors through pharmacophore-based virtual screening for the development of anti-psychotic drugs. In this study, we employed the latest discovered high-resolution crystal structure of human D, receptor to conduct active-site-analysis, build the receptor-based harmacophore model and screen the Asinex GOLD Collection database. 7 hits were purchased and tested by harmacological experiments. A novel inhibitor 04932482 with a high activity against D, receptor was obtaine [K:=(806. 75+34.58)nmol/L]. The structure analysis was conducted and the ligand-receptor interaction was further investigated by docking to guide the structure modification and optimization of compound 04932482 Keywords Dopamine D, receptor; Pharmacophore model; Database screening; Inhibitor (Ed: H, J, K)                      !  "   # $% !   &'  & !    ('   "  & )*+* , +*+-+*. +*    /   &010  0230435 /   2304 0" 3& +66 72)8, +9:-+9; ++  <  0 % <  4    =  0 % 3& )**; 7))8, )+-:**. +)/ >$>  !  #4 ?(=  "   4& #0 ! =@  & )**: 7+:8, ::.)-::.. +:A   >    % &  "0%   0 %  A        B(%30'!   &  !=      * @ '   !+2 00 41= ,   B  )** +;@   !0 C'   4/ & 23  % /& )**+ , D.*9-D.+; +./!<4E&78 !#E 478 FGF E& 7 8 FB!#&EA 47  8 # E 7  8  % &    G '   78& )*+* 7.8, :6-;D           #F EF ￾  "# 4￾  FG E ￾  FB<# E&￾  !< E ￾  #F E  AG ￾ 7+                      ! "  )*+)*: H )      #  $        )*+)*: 8  I%     I 40  3  =  0  1=I%   ?  B  %I0  =  %3 04 0I   0= 4% '  I0   4   % %3 0  4 = 1  % 0 B  '0' =   I0431I3 =      (I   2> J=   = =4==   B 14  4 1  = ' ' 0  ? 4 I%I E? = ' 0   41 = ' 0I% 1 EI3 =4 B  =3 $ %I03 =  0 = '  =  4E 0  30 1%    I= ' E  E03  ? 0=    IE? = I%I %= 0=    !  C<00   =? 9  $  I = =   = ?3 I%04 0 CI  %  !' 0  ?   $   4  ' 34    I$?  = ￾K76*DK9. M:;K.68 %05   03 $= = =  0 4=E  I    $1  '  4 = ?3=> 44 =   %= 1   = I % (  1%I=   !"# I%     IH 2%I %= 0H ?   4H B ?  =  &  +96;  0 :)