title: Homobivalent ligands of the atypical antipsychotic clozapine: design, synthesis, and pharmacological evaluation.
abstract: To date all typical and atypical antipsychotics target the dopamine D(2) receptor. Clozapine represents the best-characterized atypical antipsychotic, although it displays only moderate (submicromolar) affinity for the dopamine D(2) receptor. Herein, we present the design, synthesis, and pharmacological evaluation of three series of homobivalent ligands of clozapine, differing in the length and nature of the spacer and the point of attachment to the pharmacophore. Attachment of the spacer at the N4' position of clozapine yielded a series of homobivalent ligands that displayed spacer-length-dependent gains in affinity and activity for the dopamine D(2) receptor. The 16 and 18 atom spacer bivalent ligands were the highlight compounds, displaying marked low nanomolar receptor binding affinity (1.41 and 1.35 nM, respectively) and functional activity (23 and 44 nM), which correspond to significant gains in affinity (75- and 79-fold) and activity (9- and 5-fold) relative to the original pharmacophore, clozapine. As such these ligands represent useful tools with which to investigate dopamine receptor dimerization and the atypical nature of clozapine.
authors.affiliation: Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052 Australia.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: McRobb
authors.forename: Ian T
authors.initials: IT
authors.lastname: Crosby
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Yuriev
authors.forename: J Robert
authors.initials: JR
authors.lastname: Lane
authors.forename: Ben
authors.initials: B
authors.lastname: Capuano
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D016466:CHO Cells; D003024:Clozapine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D055503:Protein Multimerization; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D008024:Ligands; D017448:Receptors, Dopamine D2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D003024:Clozapine