Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects

Wager, Travis T.; Chappie, Thomas A.; Horton, David B.; Chandrasekaran, Ramalakshmi Y.; Samas, Brian; Dunn-Sims, Elizabeth R.; Hsu, Cathleen C.; Nawreen, Nawshaba; Vanase-Frawley, Michelle; O’Connor, Rebecca E.; Schmidt, Christopher J.; Dlugolenski, Keith; Stratman, Nancy C.; Majchrzak, Mark J.; Kormos, Bethany L.; Nguyen, David P.; Sawant-Basak, Aarti; Mead, Andy N.

doi:10.1021/acschemneuro.6b00297

Cited by 18 publications

(18 citation statements)

References 57 publications

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“…It is not as good an electron donor as PF-592379 or as good an electron acceptor as PNU-177864. This might explain the excellent properties of this new antagonist, reported previously [23]. Among all the antagonists, GSK598809 is the best electron donor.…”

Section: Resultssupporting

confidence: 66%

“…It exhibits moderate affinity for D3R with clear preference in comparison to D2R, and is considered a functional antagonist. PF-4363467 was recently reported [23] as an excellent preclinical tool to test for D3R and D2R antagonist action.…”

Section: Resultsmentioning

confidence: 99%

“…The hypothesis is that this dual pharmacological strategy modulates the cue-reward processing pathway. Concurring with this idea, a structurally unique D3R/D2R antagonist was reported recently [23]. This drug is known as PF-4363467 and attenuates the opioid drug-seeking behavior of animals trained to self-administer fentanyl.…”

Section: Introductionmentioning

confidence: 97%

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Dopamine antagonists for the treatment of drug addiction: PF-4363467 and related compounds

Martı́nez

2020

Eur J Chem

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Drug addiction refers to an out-of-control and compulsive use of substances, which can reach epidemic magnitudes. It is a health concern throughout the world and has major economic impact. Dopamine receptor agonists and antagonists have been cited as molecular targets for the treatment of drug addiction. In this report, the main idea is to analyze the new D3R/D2R ligands that are proposed for the treatment of drug abuse, in terms of their electron donor/acceptor properties. Substances catalogued as agonists represent good electron donors, whereas antagonists represent good electron acceptors. HOMO and LUMO eigenvalues indicate that more energy is necessary to remove an electron from the antagonists, and likewise more energy is gained when antagonists accept an electron. The combination of two molecules (PF-592379 and PNU-177864) produces a new compound (PF-4363467) with properties that are intermediate. Irrespective of the characteristics of the receptor, the classification of ligands is important, in order to further understanding of the reaction mechanism of these compounds. This may help in the design of new molecules for the treatment of drug addiction.

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Section: Resultssupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

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Dopamine antagonists for the treatment of drug addiction: PF-4363467 and related compounds

Martı́nez

2020

Eur J Chem

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“…We recently published the in vitro and in vivo characterization of PF-4363467 ( 1 , Table 1 ), a D3R dual antagonist with unusually high D2R receptor occupancy (86%), which translated into unique in-vivo signaling, e.g. lack of locomotor or catalepsy side effects 15 . Unlike previously reported structures of D3R antagonists, 1 does not share the same pharmacophore feature arrangement (B-A 1 -L-A 2 ) and presented some challenges in the prediction of its binding mode 15 .…”

Section: Introductionmentioning

confidence: 99%

Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs

Ferruz

Doerr

Vanase-Frawley

et al. 2018

Sci Rep

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The recent increase in the number of X-ray crystal structures of G-protein coupled receptors (GPCRs) has been enabling for structure-based drug design (SBDD) efforts. These structures have revealed that GPCRs are highly dynamic macromolecules whose function is dependent on their intrinsic flexibility. Unfortunately, the use of static structures to understand ligand binding can potentially be misleading, especially in systems with an inherently high degree of conformational flexibility. Here, we show that docking a set of dopamine D3 receptor compounds into the existing eticlopride-bound dopamine D3 receptor (D3R) X-ray crystal structure resulted in poses that were not consistent with results obtained from site-directed mutagenesis experiments. We overcame the limitations of static docking by using large-scale high-throughput molecular dynamics (MD) simulations and Markov state models (MSMs) to determine an alternative pose consistent with the mutation data. The new pose maintains critical interactions observed in the D3R/eticlopride X-ray crystal structure and suggests that a cryptic pocket forms due to the shift of a highly conserved residue, F6.52. Our study highlights the importance of GPCR dynamics to understand ligand binding and provides new opportunities for drug discovery.

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“…Current concepts suggest that dopamine appears to be associated with craving, relapse and continued drug use, as illustrated with cocaine and alcohol [21,22]. Consistently, dopamine receptor antagonists have been reported to reduce excessive drinking and addictive drug use [23]. A more direct approach to target this pathophysiologic mechanism would be to prevent the underlying dopamine surge to attenuate alcoholand drug-seeking behaviour.…”

Section: Discussionmentioning

confidence: 99%

Aldehyde Dehydrogenase 2 Anti-Sense in the Ventral Tegmental Area Reduces Alcohol Drinking

Diamond¹,

Fan²,

Arolfo³

et al. 2019

J Alcohol Drug Depend

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Background: We have reported that aldehyde dehydrogenase 2 (ALDH2) inhibitors suppress alcohol seeking and drinking in rats even in the absence of alcohol and acetaldehyde. These behavioural changes suggest that ALDH2 in brain could be a target for ANS-6637 inhibition to suppress alcohol seeking and drinking. Here we ask whether ALDH2-RNA anti-sense administered directly into the Ventral Tegmental Area (VTA) also reduces alcohol drinking. Methods: A recombinant adenoviral vector expressing rat AGS3 and specific RNA antisense against ALDH2 was injected into the VTA of actively drinking alcohol-preferring (iP) rats in a 2-bottle choice study with 10% alcohol (v/v) and water. Controls received scrambled RNA. Alcohol consumption was assayed before and after adenoviral injection. Histology confirmed cannulae implantation. Results: ALDH2 antisense microinjected in the VTA of alcohol-drinking iP rats reduces alcohol intake when compared with baseline drinking prior to antisense microinjection. Controls are unaffected. Reduction occurs between days 5 and 12 post-ALDH2 antisense microinjection with maximal effects on days 7 and 9 (31% from baseline). Rats recover baseline alcohol intake values by day 16. Conclusions: The major finding is that ALDH2 antisense in the VTA appears to reduce alcohol drinking. Consistent with previous results suggesting that ALDH2 inhibitors might reduce drinking by acting in the brain, this observation with ALDH2 antisense suggests that ALDH2 in the VTA may be an important target for pharmacologic ALDH2 inhibitors.

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Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects

Cited by 18 publications

References 57 publications

Dopamine antagonists for the treatment of drug addiction: PF-4363467 and related compounds

Dopamine antagonists for the treatment of drug addiction: PF-4363467 and related compounds

Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs

Aldehyde Dehydrogenase 2 Anti-Sense in the Ventral Tegmental Area Reduces Alcohol Drinking

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