Comparative molecular field analysis-based prediction of drug affinities at recombinant D1A dopamine receptors

Mi Youn Kim Brusniak, Robert S. Pearlman, Kim Neve, Richard E. Wilcox

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Determination of quantitative structure-activity relationships (QSAR) for affinity at particular dopamine (DA) receptors has become an even greater priority with the cloning of five DA receptor subtypes. The use of agonist affinity at recombinant receptors selectively expressed in clonal cells as the dependent variable in QSAR presents a unique opportunity for accuracy and precision in measurement of biological values. Bound conformations of 11 agonists (for which both affinity data at the recombinant D1A DA receptor and stereochemical configurations were available) were determined by alignment with a template compound, SKF38393, which shows high affinity and selectivity for D1A receptors and is fairly rigid in structure. These aligned structures suggested a 3-point pharmacophore map (one cationic nitrogen and two electronegative centers) of the D1A DA receptor. This map shows both similarities and differences when compared with a previously reported D2 DA receptor pharmacophore map based on biological data from rat brain and with a recently published map of the native D1 DA receptor using several semirigid compounds. Log(1/K(d)) values at recombinant D1A DA receptors were used as the target property for a CoMFA (comparative molecular field analysis) of the 11 aligned structures. The resulting CoMFA model yielded a cross-validated r2 (q2) value of 0.829 and a simple r2 = 0.96. In contrast, when a CoMFA model was developed for 10 of these compounds using striatal D1 K(d) values, the q2 value was reduced to 0.178. These results are consistent with the idea that drug affinity data obtained from clonal cells expressing recombinant receptors may be superior to that obtained using heterogeneous mixtures of native receptors prepared from brain membranes. The predictive utility of the CoMFA model was evaluated using several high-affinity dopamine agonists and m- and p-tyramine, two compounds with a single hydroxyl group on the aromatic ring. Predictions were fairly accurate for all compounds but the two tyramines.

Original languageEnglish (US)
Pages (from-to)850-859
Number of pages10
JournalJournal of Medicinal Chemistry
Volume39
Issue number4
DOIs
StatePublished - Feb 16 1996
Externally publishedYes

Fingerprint

Tyramine
Quantitative Structure-Activity Relationship
Dopamine Receptors
Pharmaceutical Preparations
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
Corpus Striatum
Dopamine D1 Receptors
Brain
Dopamine D2 Receptors
Dopamine Agonists
Hydroxyl Radical
Organism Cloning
Cloning
Nitrogen
Conformations
Rats
Membranes
Cells
dopamine D1A receptor
3-tyramine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Comparative molecular field analysis-based prediction of drug affinities at recombinant D1A dopamine receptors. / Brusniak, Mi Youn Kim; Pearlman, Robert S.; Neve, Kim; Wilcox, Richard E.

In: Journal of Medicinal Chemistry, Vol. 39, No. 4, 16.02.1996, p. 850-859.

Research output: Contribution to journalArticle

Brusniak, Mi Youn Kim ; Pearlman, Robert S. ; Neve, Kim ; Wilcox, Richard E. / Comparative molecular field analysis-based prediction of drug affinities at recombinant D1A dopamine receptors. In: Journal of Medicinal Chemistry. 1996 ; Vol. 39, No. 4. pp. 850-859.
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