Quantitative structure-activity relationship studies of threo-methylphenidate analogs.
Complementary two-dimensional (2D) and three-dimensional (3D) Quantitative Structure-Activity Relationship (QSAR) techniques were used to derive a preliminary model for the dopamine transporter (DAT) binding affinity of 80 racemic threo-methylphenidate (MP) analogs. A novel approach based on using the atom-level E-state indices of the 14 common scaffold atoms in a sphere exclusion protocol was used to identify a test set for 2D- and 3D-QSAR model validation. Comparative Molecular Field Analysis (CoMFA) contour maps based on the structure-activity data of the training set indicate that the 2' position of the phenyl ring cannot tolerate much steric bulk and that addition of electron-withdrawing groups to the 3' or 4' positions of the phenyl ring leads to improved DAT binding affinity. In particular, the optimal substituents were found to be those whose bulk is mainly in the plane of the phenyl ring. Substituents with significant bulk above or below the plane of the ring led to decreased binding affinity. Suggested alterations to be explored in the design of new compounds are the placement at the 3' and 4' position of the phenyl ring of electron-withdrawing groups that lie chiefly in the plane of the ring, for example, halogen substituents on the 3',4'-benzo analog, 79. A complementary 2D-QSAR approach-partial least squares analysis using a reduced set of Molconn-Z descriptors-supports the CoMFA structure-activity interpretation that phenyl ring substitution is a major determinant of DAT binding affinity. The potential usefulness of the CoMFA models was demonstrated by the prediction of the binding affinity of methyl 2-(naphthalen-1-yl)-2-(piperidin-2-yl)acetate, an analog not in the original data set, to be in good agreement with the experimental value.
Misra
Milind
M
Department of Chemistry and Environmental Science, New Jersey Institute of Technology, Newark, NJ 07102, USA.
Shi
Qing
Q
Ye
Xiaocong
X
Gruszecka-Kowalik
Ewa
E
Bu
Wei
W
Liu
Zhanzhu
Z
Schweri
Margaret M
MM
Deutsch
Howard M
HM
Venanzi
Carol A
CA
D050483:Dopamine Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D007536:Isomerism; D008774:Methylphenidate / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
D050483:Dopamine Plasma Membrane Transport Proteins; D008774:Methylphenidate