PMID- 23974015
OWN - NLM
STAT- MEDLINE
DCOM- 20140812
LR  - 20131011
IS  - 1768-3254 (Electronic)
IS  - 0223-5234 (Linking)
VI  - 68
DP  - 2013 Oct
TI  - 2,3,9- and 2,3,11-trisubstituted tetrahydroprotoberberines as D2 dopaminergic 
      ligands.
PG  - 150-66
LID - S0223-5234(13)00484-4 [pii]
LID - 10.1016/j.ejmech.2013.07.036 [doi]
AB  - Dopamine-mediated neurotransmission plays an important role in relevant 
      psychiatric and neurological disorders. Nowadays, there is an enormous interest 
      in the development of new dopamine receptors (DR) acting drugs as potential new 
      targets for the treatment of schizophrenia or Parkinson's disease. Previous 
      studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines 
      (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D2 
      dopaminergic alkaloids since they share structural similarities with dopamine. In 
      the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted 
      THPB compounds (six of them are described for the first time) and evaluated their 
      potential dopaminergic activity. Binding studies on rat striatal membranes were 
      used to evaluate their affinity and selectivity towards D1 and D2 DR and 
      establish the structure-activity relationship (SAR) as dopaminergic agents. In 
      general, all the tested THPBs with protected phenolic hydroxyls showed a lower 
      affinity for D1 and D2 DR than their corresponding homologues with free hydroxyl 
      groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs 
      (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in 
      increased affinity and selectivity towards D2 DR. This is in contrast with the 
      current study since the existence of a chlorine atom into the A-ring of the THPBs 
      caused increased affinity for D1 DR but dramatically reduced the selectivity for 
      D2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity 
      for DR than its homologue with an OH group in position 11 (9e) (250 fold for D2 
      DR). None of the compounds showed any cytotoxicity in freshly isolated human 
      neutrophils. A molecular modelling study of three representative THPBs was 
      carried out. The combination of MD simulations with DFT calculations provided a 
      clear picture of the ligand binding interactions from a structural and energetic 
      point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) 
      behave as D2 DR agonist since serine residues cluster are crucial for agonist 
      binding and receptor activation.
CI  - Copyright (c) 2013 Elsevier Masson SAS. All rights reserved.
FAU - Parraga, Javier
AU  - Parraga J
AD  - Departamento de Farmacologia, Laboratorio de Farmacoquimica, Facultad de 
      Farmacia, Universidad de Valencia, Burjassot, 46100 Valencia, Spain.
FAU - Cabedo, Nuria
AU  - Cabedo N
FAU - Andujar, Sebastian
AU  - Andujar S
FAU - Piqueras, Laura
AU  - Piqueras L
FAU - Moreno, Laura
AU  - Moreno L
FAU - Galan, Abraham
AU  - Galan A
FAU - Angelina, Emilio
AU  - Angelina E
FAU - Enriz, Ricardo D
AU  - Enriz RD
FAU - Ivorra, Maria Dolores
AU  - Ivorra MD
FAU - Sanz, Maria Jesus
AU  - Sanz MJ
FAU - Cortes, Diego
AU  - Cortes D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130811
PL  - France
TA  - Eur J Med Chem
JT  - European journal of medicinal chemistry
JID - 0420510
RN  - 0 (Ligands)
RN  - 0 (Receptors, Dopamine D2)
RN  - 0I8Y3P32UF (Berberine)
SB  - IM
MH  - Animals
MH  - Berberine/chemical synthesis/*chemistry/pharmacology
MH  - Cell Survival
MH  - Humans
MH  - Ligands
MH  - Models, Molecular
MH  - *Molecular Dynamics Simulation
MH  - Molecular Structure
MH  - Rats
MH  - Receptors, Dopamine D2/*agonists/*chemistry
OTO - NOTNLM
OT  - Dopamine receptors
OT  - MTT and cytofluorometric analysis
OT  - Structure-activity relationships cytotoxicity
OT  - Tetrahydroprotoberberines
OT  - Theoretical calculations
EDAT- 2013/08/27 06:00
MHDA- 2014/08/13 06:00
CRDT- 2013/08/27 06:00
PHST- 2013/05/13 00:00 [received]
PHST- 2013/07/23 00:00 [revised]
PHST- 2013/07/25 00:00 [accepted]
PHST- 2013/08/27 06:00 [entrez]
PHST- 2013/08/27 06:00 [pubmed]
PHST- 2014/08/13 06:00 [medline]
AID - S0223-5234(13)00484-4 [pii]
AID - 10.1016/j.ejmech.2013.07.036 [doi]
PST - ppublish
SO  - Eur J Med Chem. 2013 Oct;68:150-66. doi: 10.1016/j.ejmech.2013.07.036. Epub 2013 
      Aug 11.