Molecular properties affecting fast dissociation from the D2 receptor

Dopamine D2 receptor antagonism is the foundation of antipsychotic treatment. Antipsychotic agents vary in how fast they dissociate from the D2 receptors. It has been proposed that the liability to exhibit side effects such as extra pyramidal symptoms may be the result of a slow rate of dissociation. Compounds with a faster rate of dissociation, while still blocking efficiently the D2 receptors, will subsequently respond better to physiological surges in dopamine transmission. Therefore, work in our laboratories has focussed on identifying fast dissociating and selective D2 antagonists. Biological screening was performed to measure the affinity and extent of dissociation for a large dataset of over 1800 D2 antagonists. Subsequent univariate and multivariate statistical analysis revealed the molecular properties which differentiate fast and slow dissociating compounds. It is shown that faster dissociating antagonists are less lipophilic and have lower molecular weight. There was a clear and expected inverse relationship with extent of dissociation and binding affinity with more potent compounds tending to be slower dissociating. However, within a range of comparable affinity both fast and slow dissociating compounds were identified. After de-correlating affinity and dissociation the analysis revealed the important descriptors.

Statistical analysis reveals the important molecular properties affecting fast and slow dissociating D2 receptor antagonists.Figure optionsDownload as PowerPoint slide