Investigation of novel ropinirole analogues: Synthesis, pharmacological evaluation and computational analysis of dopamine D2 receptor functionalized congeners and homobivalent ligands

Manuela Therese Jorg, Agnieszka A Kaczor, Frankie S Mak, Kiew Ching K Lee, Antti Poso, Neil D Miller, Peter John Scammells, Benvenuto Capuano

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

Abstract

Herein, we report the development of novel functionalized congeners of ropinirole toward the design of pharmacological tools to probe structural requirements at the dopamine D2 receptor. Subsequently, we have used the functionalized amine congener 11 and synthesized and pharmacologically evaluated a series of homobivalent ligands of ropinirole with designated spacer lengths ranging from 14 to 30 atoms. The most potent homobivalent ligands (22-, 26- and 30-atom spacers) showed approximately 20- to 80-fold greater potency (EC50 = 3.9, 6.2 and 14 nM, respectively) than ropinirole (304 nM) in a [35S]GTP?S functional assay. Molecular modeling studies suggest that the observed increase in potency of the homobivalent ligands is possibly due to a bitopic binding mode involving the orthosteric site and an allosteric interaction at the dopamine D2 receptor protomer rather than bridging interactions at two orthosteric sites across a dopamine D 2 receptor dimer. This research has the potential to advance the development of structurally related bitopic ligands, biomarkers such as radioligands and fluorescently labeled probes, and furnish new homo- and heterobivalent ligands towards a better understanding of the dopamine D 2 receptor and potential novel treatment for Parkinson s disease.
Original languageEnglish
Pages (from-to)891 - 898
Number of pages8
JournalMedChemComm
Volume5
Issue number7
DOIs
Publication statusPublished - 2014

Cite this

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title = "Investigation of novel ropinirole analogues: Synthesis, pharmacological evaluation and computational analysis of dopamine D2 receptor functionalized congeners and homobivalent ligands",
abstract = "Herein, we report the development of novel functionalized congeners of ropinirole toward the design of pharmacological tools to probe structural requirements at the dopamine D2 receptor. Subsequently, we have used the functionalized amine congener 11 and synthesized and pharmacologically evaluated a series of homobivalent ligands of ropinirole with designated spacer lengths ranging from 14 to 30 atoms. The most potent homobivalent ligands (22-, 26- and 30-atom spacers) showed approximately 20- to 80-fold greater potency (EC50 = 3.9, 6.2 and 14 nM, respectively) than ropinirole (304 nM) in a [35S]GTP?S functional assay. Molecular modeling studies suggest that the observed increase in potency of the homobivalent ligands is possibly due to a bitopic binding mode involving the orthosteric site and an allosteric interaction at the dopamine D2 receptor protomer rather than bridging interactions at two orthosteric sites across a dopamine D 2 receptor dimer. This research has the potential to advance the development of structurally related bitopic ligands, biomarkers such as radioligands and fluorescently labeled probes, and furnish new homo- and heterobivalent ligands towards a better understanding of the dopamine D 2 receptor and potential novel treatment for Parkinson s disease.",
author = "Jorg, {Manuela Therese} and Kaczor, {Agnieszka A} and Mak, {Frankie S} and Lee, {Kiew Ching K} and Antti Poso and Miller, {Neil D} and Scammells, {Peter John} and Benvenuto Capuano",
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publisher = "The Royal Society of Chemistry",
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Investigation of novel ropinirole analogues: Synthesis, pharmacological evaluation and computational analysis of dopamine D2 receptor functionalized congeners and homobivalent ligands. / Jorg, Manuela Therese; Kaczor, Agnieszka A; Mak, Frankie S; Lee, Kiew Ching K; Poso, Antti; Miller, Neil D; Scammells, Peter John; Capuano, Benvenuto.

In: MedChemComm, Vol. 5, No. 7, 2014, p. 891 - 898.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Jorg, Manuela Therese

AU - Kaczor, Agnieszka A

AU - Mak, Frankie S

AU - Lee, Kiew Ching K

AU - Poso, Antti

AU - Miller, Neil D

AU - Scammells, Peter John

AU - Capuano, Benvenuto

PY - 2014

Y1 - 2014

N2 - Herein, we report the development of novel functionalized congeners of ropinirole toward the design of pharmacological tools to probe structural requirements at the dopamine D2 receptor. Subsequently, we have used the functionalized amine congener 11 and synthesized and pharmacologically evaluated a series of homobivalent ligands of ropinirole with designated spacer lengths ranging from 14 to 30 atoms. The most potent homobivalent ligands (22-, 26- and 30-atom spacers) showed approximately 20- to 80-fold greater potency (EC50 = 3.9, 6.2 and 14 nM, respectively) than ropinirole (304 nM) in a [35S]GTP?S functional assay. Molecular modeling studies suggest that the observed increase in potency of the homobivalent ligands is possibly due to a bitopic binding mode involving the orthosteric site and an allosteric interaction at the dopamine D2 receptor protomer rather than bridging interactions at two orthosteric sites across a dopamine D 2 receptor dimer. This research has the potential to advance the development of structurally related bitopic ligands, biomarkers such as radioligands and fluorescently labeled probes, and furnish new homo- and heterobivalent ligands towards a better understanding of the dopamine D 2 receptor and potential novel treatment for Parkinson s disease.

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