CoMFA-based prediction of agonist affinities at recombinant D1 vs D2 dopamine receptors

Journal of Medicinal Chemistry

Volumn 41, Issue 22, 1998, Pages 4385-4399

  Wilcox, Richard E ^a   Tseng, Tom ^a   Brusniak, Mi Youn Kim ^a   Ginsburg, Brett ^a   Pearlman, Robert S ^a   Teeter, Martha ^b   Durand, Curtiss ^c   Starr, Stephanie ^d   Neve, Kim A ^d  

^a UNIVERSITY OF TEXAS AT AUSTIN   (United States)

^b BOSTON COLLEGE   (United States)

^c VETERANS AFFAIRS MEDICAL CENTER   (United States)

^d PORTLAND VA MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 DIPROPYLAMINO 7 HYDROXYTETRALIN; APOMORPHINE; BENZAZEPINE DERIVATIVE; BROMOCRIPTINE; DOPAMINE 1 RECEPTOR; DOPAMINE 1 RECEPTOR STIMULATING AGENT; DOPAMINE 2 RECEPTOR; DOPAMINE 2 RECEPTOR STIMULATING AGENT; DRUG CARRIER; LISURIDE;

ACCURACY; ARTICLE; DOPAMINERGIC SYSTEM; DRUG RECEPTOR BINDING; DRUG STRUCTURE; HUMAN; HUMAN CELL; QUANTITATIVE STRUCTURE ACTIVITY RELATION; RECEPTOR AFFINITY; TUMOR CELL LINE;

ANIMALS; BINDING SITES; DATABASES, FACTUAL; DOPAMINE AGONISTS; HUMANS; LIGANDS; MACACA MULATTA; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PROTEIN STRUCTURE, SECONDARY; RATS; RECEPTORS, DOPAMINE D1; RECEPTORS, DOPAMINE D2; RECOMBINANT PROTEINS; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR CELLS, CULTURED;

EID: 0032561220     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9800292     Document Type: Article

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60. In the original version of the manuscript we had selected the highly rigid compound, DHX, as the D1 template. However, on the basis of a suggestion by one of the reviewers, we repeated the alignment and CoMFA for the D1 model using the higher affinity, but less conformationally constrained, compound Br-APB as template.
61. Generally, alignment of most of the training set compounds with catechol-like structures was quite good with Br-APB, whereas alignment of the ergoline compounds was more problematic. Similarly, alignment of the training set compounds possessing ergoline features with bromocriptine was generally excellent; in contrast, alignment of the catechol-like compounds was less successful. The strategy that seemed most successful empirically was to take the compound of the dissimilar structural class which had the smallest residual value in the initial CoMFA and use it as a pseudo template to improve the alignment of structurally related compounds.
62. 25
63. 2 values to the models reported here. Also, the pharmacophore maps used to assist in developing the search queries were very similar to those associated with the final models. It is important to note that these good predictions occurred only with conformers of the two compounds which were well fit to the template compound for each CoMFA. Other conformers or those less well fit had predicted values which deviated to a significantly greater extent from the measured values (data not shown).
64. 2 values.
65. One of the reviewers suggested that we obtain these two compounds and measure their affinities. Unfortunately, Schering had already discontinued testing with them, and we were unable to obtain them.
66. In the D1 receptor, the corresponding residues are Phe, Val, and Trp, with no potential hydrogen-bonding oxygens available.