Design, synthesis, and evaluation of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamides as selective dopamine D3 receptor ligands

Chen, Peng‐Jen; Taylor, Michelle; Griffin, Suzy A.; Amani, Armaghan; Hayatshahi, Hamed S.; Korzekwa, Kenneth R.; Ye, Min; Mach, Robert H.; Jin, Liu; Luedtke, Robert R.; Gordon, John; Blass, Benjamin E.

doi:10.1016/j.bmcl.2019.07.020

Cited by 23 publications

(38 citation statements)

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“…BP1.4979 has been shown to achieve high, dose dependent D3R occupancy in the human brain [ 156 ]. Among N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamides [ 157 ], MC-25-41 (D3R Ki: 0.5 nM, 1,486-fold selectivity over D2Rs) has been identified as potent and long acting partial agonist for the D3R. MC-25-41 has been found to reduce motivation for cocaine in rats and the long half-life of the drug may render it useful in the treatment of cocaine abuse [ 158 ].…”

Section: D3r Ligandsmentioning

confidence: 99%

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

et al. 2021

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Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson’s disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.

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Section: D3r Ligandsmentioning

confidence: 99%

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

et al. 2021

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“…The pharmacokinetic profile and in vivo pharmacology of MC-25-41 suggest that it may be a useful pre-clinical lead compound [23]. MC-25-41 has sub-nanomolar affinity for D3Rs (K i = 0.50 nM), high selectivity for D3 over D2 receptors (1486 fold), and a half-life in male Sprague-Dawley rats of over 10 h [23]. Beyond the selectivity for D3R over D2R, MC-25-41 has >20,000-fold selectivity for D3R over D1R or D5R and >1600-fold selectivity for D3R over D4R.…”

Section: Discussionmentioning

confidence: 99%

“…MC-25-41 was prepared according to the methods described in our previous publication [ 23 ] and dissolved in 20% w / v cyclodextrin and 3% v / v 1M hydrochloric acid and was delivered IP at a volume of 1 mL/kg. Cocaine hydrochloride (RTI International, Research Triangle Park, NC, USA) was dissolved in bacteriostatic saline and additionally filtered through 0.3 μm filters when administered IV.…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, we would like to thank Raul Garcia, Samantha Scott, and Taleen Der-Ghazarian for their assistance with catheter implantation surgeries. Additionally, MC-25-41 offsite binding data was provided by the National Institute of Mental Health Psychoactive Drug Screening Program [ 23 ].…”

Section: Acknowledgmentsmentioning

confidence: 99%

“…Here, we report the effects of the D3R-selective partial agonist, MC-25-41, on reinforcer intake in male rats tested under either low-effort or increasing-effort schedules of cocaine and/or sucrose reinforcement. MC-25-41 demonstrates high affinity for the D3R (K i = 0.50 nM), selectivity for the D3R over the D2R (1486-fold), a prolonged half-life (>60 m in human and rat liver microsome assays), and low efficacy (19.4% maximum activity) in the forskolin-dependent adenylyl cyclase inhibition assay ([ 23 ]; referred to as “13r”; Figure 1 ). The low-effort reinforcement schedule used in the present study was a VI 60 s multiple schedule of cocaine and sucrose reinforcement.…”

Section: Introductionmentioning

confidence: 99%

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The Long-Acting D3 Partial Agonist MC-25-41 Attenuates Motivation for Cocaine in Sprague-Dawley Rats

et al. 2020

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The dopamine D3 receptor is a prime target for developing treatments for cocaine use disorders (CUDs). In this study, we conducted a pre-clinical investigation of the therapeutic potential of a long-acting, D3 receptor partial agonist, MC-25-41. Male rats were pre-treated with MC-25-41 (vehicle, 1.0, 3.0, 5.6, or 10 mg/kg, intraperitoneal (IP)) five minutes prior to tests of cocaine or sucrose intake on either a progressive ratio schedule of reinforcement or a variable interval 60 s multiple schedule consisting of 4, 15-min components with sucrose or cocaine available in alternating components. A separate cohort of rats was tested on a within-session, dose-reduction procedure to determine the effects of MC-25-41 on demand for cocaine using a behavioral economics analysis. Finally, rats were tested for effects of MC-25-41 on spontaneous and cocaine-induced locomotion. MC-25-41 failed to alter locomotion, but reduced reinforcement rates for both cocaine and sucrose on the low-effort, multiple schedule. However, on the higher-effort, progressive ratio schedule of cocaine reinforcement, MC-25-41 reduced infusions, and active lever presses at doses that did not alter sucrose intake. The behavioral economics analysis showed that MC-25-41 also increased cocaine demand elasticity compared to vehicle, indicating a reduction in consumption as price increases. Together, these results suggest that similar to other D3-selective antagonists and partial agonists, MC-25-41 reduces motivation for cocaine under conditions of high cost but has the added advantage of a long half-life (>10 h). These findings suggest that MC-25-41 may be a suitable pre-clinical lead compound for development of medications to treat CUDs.

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Synthesis, in silico, and in vitro studies of novel dopamine D₂ and D₃ receptor ligands

Elek

Djoković

Frank

et al. 2021

Archiv der Pharmazie

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Dopamine is an important neurotransmitter in the human brain and its altered concentrations can lead to various neurological diseases. We studied the binding of novel compounds at the dopamine D 2 (D 2 R) and D 3 (D 3 R) receptor subtypes, which belong to the D 2 -like receptor family. The synthesis, in silico, and in vitro characterization of 10 dopamine receptor ligands were performed. Novel ligands were docked into the D 2 R and D 3 R crystal structures to examine the precise binding mode. A quantum mechanics/molecular mechanics study was performed to gain insights into the nature of the intermolecular interactions between the newly introduced pentafluorosulfanyl (SF 5 ) moiety and D 2 R and D 3 R. A radioligand displacement assay determined that all of the ligands showed moderate-to-low nanomolar affinities at D 2 R and D 3 R, with a slight preference for D 3 R, which was confirmed in the in silico studies. N-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-4-(pentafluoro-λ6-sulfanyl)benzamide (7i) showed the highest D 3 R affinity and selectivity (pK i values of 7.14 [D 2 R] and 8.42 [D 3 R]).

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Design, synthesis, and evaluation of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamides as selective dopamine D3 receptor ligands

Cited by 23 publications

References 27 publications

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

The Long-Acting D3 Partial Agonist MC-25-41 Attenuates Motivation for Cocaine in Sprague-Dawley Rats

Synthesis, in silico, and in vitro studies of novel dopamine D₂ and D₃ receptor ligands

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Design, synthesis, and evaluation of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamides as selective dopamine D3 receptor ligands

Cited by 23 publications

References 27 publications

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

The Long-Acting D3 Partial Agonist MC-25-41 Attenuates Motivation for Cocaine in Sprague-Dawley Rats

Synthesis, in silico, and in vitro studies of novel dopamine D2 and D3 receptor ligands

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Synthesis, in silico, and in vitro studies of novel dopamine D₂ and D₃ receptor ligands