Homobivalent ligands of the atypical antipsychotic clozapine: Design, synthesis, and pharmacological evaluation

Fiona Michelle McRobb, Ian Travers Crosby, Elizabeth Yuriev, Jonathan Robert David Lane, Benvenuto Capuano

Research output: Contribution to journal › Article › Research › peer-review

33 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1622 - 1634
Number of pages13
JournalJournal of Medicinal Chemistry
Volume55
Issue number4
DOIs
Publication statusPublished - 2012

Cite this

McRobb, Fiona Michelle ; Crosby, Ian Travers ; Yuriev, Elizabeth ; Lane, Jonathan Robert David ; Capuano, Benvenuto. / Homobivalent ligands of the atypical antipsychotic clozapine: Design, synthesis, and pharmacological evaluation. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 4. pp. 1622 - 1634.
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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.",
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McRobb, FM, Crosby, IT, Yuriev, E, Lane, JRD & Capuano, B 2012, 'Homobivalent ligands of the atypical antipsychotic clozapine: Design, synthesis, and pharmacological evaluation', Journal of Medicinal Chemistry, vol. 55, no. 4, pp. 1622 - 1634. https://doi.org/10.1021/jm201420s

Homobivalent ligands of the atypical antipsychotic clozapine: Design, synthesis, and pharmacological evaluation. / McRobb, Fiona Michelle; Crosby, Ian Travers; Yuriev, Elizabeth; Lane, Jonathan Robert David; Capuano, Benvenuto.

In: Journal of Medicinal Chemistry, Vol. 55, No. 4, 2012, p. 1622 - 1634.

Research output: Contribution to journal › Article › Research › peer-review

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T1 - Homobivalent ligands of the atypical antipsychotic clozapine: Design, synthesis, and pharmacological evaluation

AU - McRobb, Fiona Michelle

AU - Crosby, Ian Travers

AU - Yuriev, Elizabeth

AU - Lane, Jonathan Robert David

AU - Capuano, Benvenuto

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

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McRobb FM, Crosby IT, Yuriev E, Lane JRD, Capuano B. Homobivalent ligands of the atypical antipsychotic clozapine: Design, synthesis, and pharmacological evaluation. Journal of Medicinal Chemistry. 2012;55(4):1622 - 1634. https://doi.org/10.1021/jm201420s

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