Beyond Small-Molecule SAR

Keck, Thomas M.; Burzynski, Caitlin; Shi, Lei; Newman, Amy Hauck

doi:10.1016/b978-0-12-420118-7.00007-x

Cited by 42 publications

(32 citation statements)

References 128 publications

(205 reference statements)

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“…11,12 Specifically, the high-resolution crystal structure of D 3 R can be used to guide the design of novel D 3 R-selective compounds with predicted efficacy. 11,13,14 In the crystal structure, eticlopride occupies the orthosteric binding site (OBS) defined by side chains from transmembrane helices II, III, IV, V, VI and VII.…”

Section: Introductionmentioning

confidence: 99%

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Highly Selective Dopamine D₃ Receptor (D₃R) Antagonists and Partial Agonists Based on Eticlopride and the D₃R Crystal Structure: New Leads for Opioid Dependence Treatment

et al. 2016

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The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the dopamine D3 receptor (D3R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse. Herein, we report a series of novel and D3R crystal structure-guided 4-phenylpiperazines with exceptionally high D3R affinities and/or selectivities with varying efficacies. Lead compound 19 was selected based on its in vitro profile: D3R Ki = 6.84 nM, 1700 fold D3R versus D2R binding selectivity, and its metabolic stability in mouse microsomes. Compound 19 inhibited oxycodone-induced hyperlocomotion in mice and reduced oxycodone-induced locomotor sensitization. In addition, pretreatment with 19 also dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference (CPP) in rats. These findings support the D3R as a target for opioid dependence treatment and compound 19 as a new lead molecule for development.

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Section: Introductionmentioning

confidence: 99%

“…22,23 Hence, the combination of small molecule SAR and clues from the D 3 R crystal structure can produce structurally and pharmacologically unique molecules with D 3 R or potentially D 2 R selectivities and differing functional efficacies. 12 …”

Section: Introductionmentioning

confidence: 99%

Highly Selective Dopamine D₃ Receptor (D₃R) Antagonists and Partial Agonists Based on Eticlopride and the D₃R Crystal Structure: New Leads for Opioid Dependence Treatment

et al. 2016

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“…Our efforts on the 4-phenylpiperazine class of compounds have led to high-affinity D 3 R-selective compounds with varying efficacies. 7, 8 …”

Section: Introductionmentioning

confidence: 99%

Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D₃ Receptor

et al. 2017

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Both dopamine D3 receptor (D3R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (R)-enantiomers are antagonists/weak partial agonists whereas the (S)-enantiomers are much more efficacious. To investigate the structural basis of partial agonism, we performed comparative microsecond-scale molecular dynamics simulations starting from the inactive state of D3R in complex with these enantiomers. Analysis of the simulation results reveals common structural rearrangements near the ligand binding site induced by the bound (S)-enantiomers, but not by the (R)-enantiomers, that are features of partially activated receptor conformations. These receptor models bound with partial agonists may be useful for structure-based design of compounds with tailored efficacy profiles.

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“…The discovery and development of D 3 -selective ligands as potential medications was initiated in the late 1990s with the introduction of NGB 2904, BP 897, and SB277011A, followed by an explosion of medicinal chemistry and structure-activity relationship (SAR) information (reviewed in (Boeckler and Gmeiner, 2006; Keck et al, 2014; Lober et al, 2011; Micheli and Heidbreder, 2013)). Through extensive investigation it became apparent that an extended-length molecule that included a tertiary amine on one end and an extended aryl or alkyl amide on the other, linked together with a four atom linking chain was required for the 4-phenylpiperazine class of D 3 -selective ligands; one of the most studied.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the binding and functional properties of extended length D3 dopamine receptor-selective antagonists

Furman

Roof

Moritz

et al. 2015

European Neuropsychopharmacology

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The D3 dopamine receptor represents an important target in drug addiction in that reducing receptor activity may attenuate the self-administration of drugs and/or disrupt drug or cue-induced relapse. Medicinal chemistry efforts have led to the development of D3 preferring antagonists and partial agonists that are >100-fold selective vs. the closely related D2 receptor, as best exemplified by extended-length 4-phenylpiperazine derivatives. Based on the D3 receptor crystal structure, these molecules are known to dock to two sites on the receptor where the 4-phenylpiperazine moiety binds to the orthosteric site and an extended aryl amide moiety docks to a secondary binding pocket. The bivalent nature of the receptor binding of these compounds is believed to contribute to their D3 selectivity. In this study, we examined if such compounds might also be “bitopic” such that their aryl amide moieties act as allosteric modulators to further enhance the affinities of the full-length molecules for the receptor. First, we deconstructed several extended-length D3-selective ligands into fragments, termed “synthons”, representing either orthosteric or secondary aryl amide pharmacophores and investigated their effects on D3 receptor binding and function. The orthosteric synthons were found to inhibit radioligand binding and to antagonize dopamine activation of the D3 receptor, albeit with lower affinities than the full-length compounds. Notably, the aryl amide-based synthons had no effect on the affinities or potencies of the orthosteric synthons, nor did they have any effect on receptor activation by dopamine. Additionally, pharmacological investigation of the full-length D3-selective antagonists revealed that these compounds interacted with the D3 receptor in a purely competitive manner. Our data further support that the 4-phenylpiperazine D3-selective antagonists are bivalent and that their enhanced affinity for the D3 receptor is due to binding at both the orthosteric site as well as a secondary binding pocket. Importantly, however, their interactions at the secondary site do not allosterically modulate their binding to the orthosteric site.

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Beyond Small-Molecule SAR

Cited by 42 publications

References 128 publications

Highly Selective Dopamine D₃ Receptor (D₃R) Antagonists and Partial Agonists Based on Eticlopride and the D₃R Crystal Structure: New Leads for Opioid Dependence Treatment

Highly Selective Dopamine D₃ Receptor (D₃R) Antagonists and Partial Agonists Based on Eticlopride and the D₃R Crystal Structure: New Leads for Opioid Dependence Treatment

Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D₃ Receptor

Investigation of the binding and functional properties of extended length D3 dopamine receptor-selective antagonists

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Beyond Small-Molecule SAR

Cited by 42 publications

References 128 publications

Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment

Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment

Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D3 Receptor

Investigation of the binding and functional properties of extended length D3 dopamine receptor-selective antagonists

Contact Info

Product

Resources

About

Highly Selective Dopamine D₃ Receptor (D₃R) Antagonists and Partial Agonists Based on Eticlopride and the D₃R Crystal Structure: New Leads for Opioid Dependence Treatment

Highly Selective Dopamine D₃ Receptor (D₃R) Antagonists and Partial Agonists Based on Eticlopride and the D₃R Crystal Structure: New Leads for Opioid Dependence Treatment

Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D₃ Receptor