Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D 3 Receptor (D 3 R) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs)

Sean W. Reilly, Aladdin A. Riad, Chia Ju Hsieh, Kristoffer Sahlholm, Daniel A. Jacome, Suzy Griffin, Michelle Taylor, Chi Chang Weng, Kuiying Xu, Nathan Kirschner, Robert T. Luedtke, Christopher Parry, Shipra Malhotra, John Karanicolas, Robert H. Mach

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Abstract

Previously, we reported a 3-(2-methoxyphenyl)-9-(3-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio)propyl)-3,9-diazaspiro[5.5]undecane (1) compound with excellent dopamine D 3 receptor (D 3 R) affinity (D 3 R K i = 12.0 nM) and selectivity (D 2 R/D 3 R ratio = 905). Herein, we present derivatives of 1 with comparable D 3 R affinity (32, D 3 R K i = 3.2 nM, D 2 R/D 3 R ratio = 60) and selectivity (30, D 3 R K i = 21.0 nM, D 2 R/D 3 R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D 3 R affinity (K i = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D 3 R K i = 23.9 nM), 1 was found to be more selective for the D 3 R among D 1 - and D 2 -like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing D 3 R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D 3 R ligand systems to minimize drug promiscuity at other aminergic GPCR sites.

Original languageEnglish
Pages (from-to)5132-5147
Number of pages16
JournalJournal of Medicinal Chemistry
Volume62
Issue number10
DOIs
StatePublished - 23 May 2019

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G-Protein-Coupled Receptors
Dopamine
Ligands
Adrenergic Agents
Pharmaceutical Preparations
piperazine
undecane

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Reilly, Sean W. ; Riad, Aladdin A. ; Hsieh, Chia Ju ; Sahlholm, Kristoffer ; Jacome, Daniel A. ; Griffin, Suzy ; Taylor, Michelle ; Weng, Chi Chang ; Xu, Kuiying ; Kirschner, Nathan ; Luedtke, Robert T. ; Parry, Christopher ; Malhotra, Shipra ; Karanicolas, John ; Mach, Robert H. / Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D 3 Receptor (D 3 R) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs) In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 10. pp. 5132-5147.
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title = "Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D 3 Receptor (D 3 R) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs)",
abstract = "Previously, we reported a 3-(2-methoxyphenyl)-9-(3-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio)propyl)-3,9-diazaspiro[5.5]undecane (1) compound with excellent dopamine D 3 receptor (D 3 R) affinity (D 3 R K i = 12.0 nM) and selectivity (D 2 R/D 3 R ratio = 905). Herein, we present derivatives of 1 with comparable D 3 R affinity (32, D 3 R K i = 3.2 nM, D 2 R/D 3 R ratio = 60) and selectivity (30, D 3 R K i = 21.0 nM, D 2 R/D 3 R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D 3 R affinity (K i = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D 3 R K i = 23.9 nM), 1 was found to be more selective for the D 3 R among D 1 - and D 2 -like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing D 3 R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D 3 R ligand systems to minimize drug promiscuity at other aminergic GPCR sites.",
author = "Reilly, {Sean W.} and Riad, {Aladdin A.} and Hsieh, {Chia Ju} and Kristoffer Sahlholm and Jacome, {Daniel A.} and Suzy Griffin and Michelle Taylor and Weng, {Chi Chang} and Kuiying Xu and Nathan Kirschner and Luedtke, {Robert T.} and Christopher Parry and Shipra Malhotra and John Karanicolas and Mach, {Robert H.}",
year = "2019",
month = "5",
day = "23",
doi = "10.1021/acs.jmedchem.9b00412",
language = "English",
volume = "62",
pages = "5132--5147",
journal = "Journal of Medicinal Chemistry",
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Reilly, SW, Riad, AA, Hsieh, CJ, Sahlholm, K, Jacome, DA, Griffin, S, Taylor, M, Weng, CC, Xu, K, Kirschner, N, Luedtke, RT, Parry, C, Malhotra, S, Karanicolas, J & Mach, RH 2019, ' Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D 3 Receptor (D 3 R) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs) ', Journal of Medicinal Chemistry, vol. 62, no. 10, pp. 5132-5147. https://doi.org/10.1021/acs.jmedchem.9b00412

Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D 3 Receptor (D 3 R) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs) . / Reilly, Sean W.; Riad, Aladdin A.; Hsieh, Chia Ju; Sahlholm, Kristoffer; Jacome, Daniel A.; Griffin, Suzy; Taylor, Michelle; Weng, Chi Chang; Xu, Kuiying; Kirschner, Nathan; Luedtke, Robert T.; Parry, Christopher; Malhotra, Shipra; Karanicolas, John; Mach, Robert H.

In: Journal of Medicinal Chemistry, Vol. 62, No. 10, 23.05.2019, p. 5132-5147.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D 3 Receptor (D 3 R) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs)

AU - Reilly, Sean W.

AU - Riad, Aladdin A.

AU - Hsieh, Chia Ju

AU - Sahlholm, Kristoffer

AU - Jacome, Daniel A.

AU - Griffin, Suzy

AU - Taylor, Michelle

AU - Weng, Chi Chang

AU - Xu, Kuiying

AU - Kirschner, Nathan

AU - Luedtke, Robert T.

AU - Parry, Christopher

AU - Malhotra, Shipra

AU - Karanicolas, John

AU - Mach, Robert H.

PY - 2019/5/23

Y1 - 2019/5/23

N2 - Previously, we reported a 3-(2-methoxyphenyl)-9-(3-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio)propyl)-3,9-diazaspiro[5.5]undecane (1) compound with excellent dopamine D 3 receptor (D 3 R) affinity (D 3 R K i = 12.0 nM) and selectivity (D 2 R/D 3 R ratio = 905). Herein, we present derivatives of 1 with comparable D 3 R affinity (32, D 3 R K i = 3.2 nM, D 2 R/D 3 R ratio = 60) and selectivity (30, D 3 R K i = 21.0 nM, D 2 R/D 3 R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D 3 R affinity (K i = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D 3 R K i = 23.9 nM), 1 was found to be more selective for the D 3 R among D 1 - and D 2 -like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing D 3 R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D 3 R ligand systems to minimize drug promiscuity at other aminergic GPCR sites.

AB - Previously, we reported a 3-(2-methoxyphenyl)-9-(3-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio)propyl)-3,9-diazaspiro[5.5]undecane (1) compound with excellent dopamine D 3 receptor (D 3 R) affinity (D 3 R K i = 12.0 nM) and selectivity (D 2 R/D 3 R ratio = 905). Herein, we present derivatives of 1 with comparable D 3 R affinity (32, D 3 R K i = 3.2 nM, D 2 R/D 3 R ratio = 60) and selectivity (30, D 3 R K i = 21.0 nM, D 2 R/D 3 R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D 3 R affinity (K i = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D 3 R K i = 23.9 nM), 1 was found to be more selective for the D 3 R among D 1 - and D 2 -like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing D 3 R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D 3 R ligand systems to minimize drug promiscuity at other aminergic GPCR sites.

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U2 - 10.1021/acs.jmedchem.9b00412

DO - 10.1021/acs.jmedchem.9b00412

M3 - Article

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SP - 5132

EP - 5147

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -