COMFA-BASED PREDICTION OF AGONIST AFFINITIES AT RECOMBINANT D1 VS D2 DOPAMINE-RECEPTORS

We have previously shown that using agonist affinity at recombinant re ceptors selectively expressed in clonal cells as the dependent variabl e in three-dimensional quantitative structure-activity relationship st udies (3D-QSAR) presents a unique opportunity for accuracy and precisi on in measurement. Thus, a comparison of affinity's structural determi nants for a set of compounds at two different recombinant dopamine rec eptors represents an attainable goal for 3D-QSAR. A molecular database of bound conformations of 16 structurally diverse agonists was establ ished by alignment with a high-affinity template compound for the D1 r eceptor, 3-allyl-6-bromo-7 hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-benz azepin. A second molecular database of the bound conformations of the same compounds was established against a second template for the D2 re ceptor, bromocriptine. These aligned structures suggested three-point pharmacophore maps tone cationic nitrogen and two electronegative cent ers) for the two dopamine receptors, which differed primarily in the h eight of the nitrogen above the plane of the catechol ring and in the nature of the hydrogen-bonding region. The In(1/K-L) values for the lo w-affinity agonist binding conformation at recombinant D1 and D2 dopam ine receptors stably expressed in C6 glioma cells were used as the tar get property for the CoMFA (comparative molecular field analysis) of t he 16 aligned structures. The resulting CoMFA models yielded cross-val idated R-2 (q(2)) values (standard error of prediction) of 0.879 (1.47 1, with five principal components) and 0.834 (1.652, with five princip al components) for D1 and D2 affinity, respectively. The simple R2 val ues (standard error of the estimate) were 0.994 (0.323) and 0.999 (0.1 16), respectively, for D1 and D2 receptor. F values were 341 and 2465 for D1 and D2 models, respectively, with 5 and 10 df. The predictive u tility of the CoMFA model was evaluated at both receptors using the do pamine agonists, apomorphine and 7-OH-DPAT. Predictions of K-L were ac curate at both receptors. Flexible 3D searches of several chemical dat abases (NCI, MDDR, CMC, ACD, and Maybridge) were done using basic phar macophore models at each receptor to determine the similarity of hit l ists between the two models. The D1 and D2 models yielded different li sts of lead compounds. Several of the lead compounds closely resembled high-affinity training set compounds. Finally, homology modeling of a gonist binding to the D2 receptor revealed some consistencies and inco nsistencies with the CoMFA-derived D2 model and provided a possible ra tionale for features of the D2 CoMFA contour map. Together these resul ts suggest that CoMFA-homology based models may provide useful insight s concerning differential agonist-receptor interactions at related rec eptors. The results also suggest that comparisons of CoMFA models for two structurally related receptors may be a fruitful approach for diff erential QSAR.