Comparative structure–activity relationships of benztropine analogues at the dopamine transporter and histamine H1 receptors

Benztropine (BZT) and its analogues inhibit dopamine uptake and bind with moderate to high affinity to the dopamine transporter (DAT). However, many of these compounds, in contrast to other monoamine uptake inhibitors, lack cocaine-like behavioral effects and fail to potentiate the effects of cocaine. The BZT analogues also exhibit varied binding affinities for muscarinic M1 and histamine H1 receptors. In this study, a comparative analysis was conducted of pharmacophoric features with respect to the activities of BZT analogues at the DAT and at the histamine H1 receptor. The BZT analogues showed a wide range of histamine H1 receptor (Ki = 16–37,600 nM) and DAT (Ki = 8.5–6370 nM) binding affinities. A stereoselective histamine H1-antagonist pharmacophore, using a five-point superimposition of classical antagonists on the template, cyproheptadine, was developed. A series of superimpositions and comparisons were performed with various analogues of BZT. In general, smaller substituents were well tolerated on the aromatic rings of the diphenyl methoxy group for both the DAT and H1 receptor, however, for the H1 receptor, substitution at only one of the aromatic rings was preferred. The substituents at the 2- and N-positions of the tropane ring were preferred for DAT, however, these groups seem to overlap receptor essential regions in the histamine H1 receptor. Molecular models at the DAT and the histamine H1 receptor provide further insight into the structural requirements for binding affinity and selectivity that can be implemented in future drug design.

Many benztropine analogues bind with high affinity to the dopamine transporter (DAT). They also show a wide range (Ki = 16–37,600 nM) of binding affinities at the histamine H1 receptor. A structural comparison of activity and selectivity at the DAT and the histamine H1 receptor was performed in order to identify structural requirements and differences for optimal binding to each site and selectivity for the DAT.Figure optionsDownload as PowerPoint slide