title: Molecular properties affecting fast dissociation from the D2 receptor.
abstract: Dopamine D(2) receptor antagonism is the foundation of antipsychotic treatment. Antipsychotic agents vary in how fast they dissociate from the D(2) 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 D(2) receptors, will subsequently respond better to physiological surges in dopamine transmission. Therefore, work in our laboratories has focussed on identifying fast dissociating and selective D(2) antagonists. Biological screening was performed to measure the affinity and extent of dissociation for a large dataset of over 1800 D(2) 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.
authors.affiliation: Research Informatics, Janssen Research & Development, Janssen-Cilag S.A., Calle Jarama 75, Poligono Industrial, Toledo 45007, Spain. gtresade@its.jnj.com
authors.forename: Gary
authors.initials: G
authors.lastname: Tresadern
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Bartolome
authors.forename: Gregor J
authors.initials: GJ
authors.lastname: Macdonald
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
mesh_terms: D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004334:Drug Administration Schedule; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2