Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D3 Receptor (D3R) 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 R. 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 D3 receptor (D3R) affinity (D3R Ki = 12.0 nM) and selectivity (D2R/D3R ratio = 905). Herein, we present derivatives of 1 with comparable D3R affinity (32, D3R Ki = 3.2 nM, D2R/D3R ratio = 60) and selectivity (30, D3R Ki = 21.0 nM, D2R/D3R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D3R affinity (Ki = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D3R Ki = 23.9 nM), 1 was found to be more selective for the D3R among D1- and D2-like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing D3R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D3R 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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Dopamine D3 Receptors
G-Protein-Coupled Receptors
Ligands
Adrenergic Agents
Pharmaceutical Preparations
piperazine
undecane

Cite this

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 R. ; Parry, Christopher ; Malhotra, Shipra ; Karanicolas, John ; Mach, Robert H. / Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D3 Receptor (D3R) 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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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 D3 receptor (D3R) affinity (D3R Ki = 12.0 nM) and selectivity (D2R/D3R ratio = 905). Herein, we present derivatives of 1 with comparable D3R affinity (32, D3R Ki = 3.2 nM, D2R/D3R ratio = 60) and selectivity (30, D3R Ki = 21.0 nM, D2R/D3R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D3R affinity (Ki = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D3R Ki = 23.9 nM), 1 was found to be more selective for the D3R among D1- and D2-like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing D3R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D3R 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 R.} and Christopher Parry and Shipra Malhotra and John Karanicolas and Mach, {Robert H.}",
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doi = "10.1021/acs.jmedchem.9b00412",
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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, RR, Parry, C, Malhotra, S, Karanicolas, J & Mach, RH 2019, 'Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D3 Receptor (D3R) 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 D3 Receptor (D3R) 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 R.; 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 journalArticle

TY - JOUR

T1 - Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D3 Receptor (D3R) 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 R.

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 D3 receptor (D3R) affinity (D3R Ki = 12.0 nM) and selectivity (D2R/D3R ratio = 905). Herein, we present derivatives of 1 with comparable D3R affinity (32, D3R Ki = 3.2 nM, D2R/D3R ratio = 60) and selectivity (30, D3R Ki = 21.0 nM, D2R/D3R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D3R affinity (Ki = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D3R Ki = 23.9 nM), 1 was found to be more selective for the D3R among D1- and D2-like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing D3R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D3R 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 D3 receptor (D3R) affinity (D3R Ki = 12.0 nM) and selectivity (D2R/D3R ratio = 905). Herein, we present derivatives of 1 with comparable D3R affinity (32, D3R Ki = 3.2 nM, D2R/D3R ratio = 60) and selectivity (30, D3R Ki = 21.0 nM, D2R/D3R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D3R affinity (Ki = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D3R Ki = 23.9 nM), 1 was found to be more selective for the D3R among D1- and D2-like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing D3R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D3R ligand systems to minimize drug promiscuity at other aminergic GPCR sites.

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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