Dopamine D3 receptor selective antagonists/partial agonists and uses thereof
Inventors
Newman, Amy Hauck • Kumar, Vivek • Shaik, Anver Basha
Assignees
US Department of Health and Human Services
Publication Number
US-12097196-B2
Publication Date
2024-09-24
Expiration Date
2039-09-09
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Abstract
Disclosed herein are novel methods of treating pain in a patient in need thereof by providing to the patient a selective dopamine D3 receptor antagonist/partial agonist which when used with an opioid analgesic, can mitigate the development of opioid dependence, by preventing the need for dose escalation while either maintaining the opioid analgesic effect or providing analgesia with a lower dose of the opioid. In addition, the D3 antagonists/partial agonists described herein may be used to augment the effectiveness of current Medication Assisted Treatment regimens (e.g. methadone or buprenorphine) for the treatment of opioid use disorders.
Core Innovation
The invention disclosed involves the use of selective dopamine D3 receptor antagonist/partial agonist compounds, particularly represented by compounds of Formula (I) and (II), in combination with opioid analgesics or Medication Assisted Treatment (MAT) agents for the treatment of pain and opioid use disorders (OUD). These D3 receptor selective antagonists/partial agonists, when used with opioid analgesics, can mitigate the development of opioid dependence by preventing the need for dose escalation and either maintaining opioid analgesic effect or providing analgesia with a lower opioid dose.
Furthermore, the D3 receptor antagonists/partial agonists can augment the effectiveness of current MAT regimens such as methadone or buprenorphine for treating opioid use disorders. The compounds exhibit high affinity and selectivity for the dopamine D3 receptor, with improved pharmacological properties and metabolic stability over prior ligands, enabling lower doses with limited side effects. The compounds can be administered prior to, concurrently, or after opioid analgesic or MAT agent administration, and may be formulated as pharmaceutical compositions or kits for clinical use.
Claims Coverage
The patent contains one independent claim focusing on a method of treating pain involving a combination treatment.
Method of treating pain using opioid analgesic with dopamine D3 receptor selective antagonist/partial agonist compound
A method comprising providing a therapeutically effective amount of an opioid analgesic or pharmaceutically acceptable salt and a therapeutically effective amount of a compound of Formula (I), including stereoisomers and pharmaceutically acceptable salts, to a human in need thereof.
Specific variants of the compound of Formula (I)
The method includes use of compounds of Formula (I) with specific substituents such as R1, R2, R3 values and Ar groups including benzofuranyl, benzothienyl, imidazolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, or indolyl, optionally substituted, described in sub-points a) through j).
Specific named compounds of Formula (I) for treatment
The method uses particular compounds of Formula (I), including N-(4-(4-(2-Chloro-3-ethylphenyl)piperazin-1-yl)butyl)-1H-indole-2-carboxamide, N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide (29), and related analogs, as stereoisomers or pharmaceutically acceptable salts.
Use of specific enantiomers of compounds of Formula (I)
The method can include use of racemic or enantiomerically pure forms such as (R)-29 and (S)-29 and other analogs within the series.
Use of a wide range of opioid analgesics
The opioid analgesic provided may be any of a list including bremazocine, butorphanol, carfentanyl, codeine, buprenorphine, fentanyl, morphine, oxycodone, tramadol and others.
Dosing regimen and duration
The method includes daily administration of the compound of Formula (I), optionally starting prior to opioid analgesic initiation, continuing during opioid therapy and optionally after discontinuation for up to 10 or more days.
Formulation and administration modes
The opioid analgesic and compound of Formula (I) may be formulated as a single pharmaceutical composition or separate compositions, administered via oral, topical, parenteral routes, including injections, inhalable forms, transdermal patches and others.
Use with Medication Assisted Treatment agents
The method may further comprise providing Medication Assisted Treatment agents such as methadone, buprenorphine, naloxone, naltrexone or levo-alpha acetyl methadol along with the compound of Formula (I).
The independent claim broadly covers a method of treating pain by administering a combination of opioid analgesics and selective dopamine D3 receptor antagonist/partial agonist compounds of Formula (I) or their stereoisomers and salts, with detailed features regarding compound structure, opioid analgesic types, dosing regimens, formulations, and optional use with Medication Assisted Treatment agents.
Stated Advantages
The compounds exhibit high potency and selectivity for the dopamine D3 receptor with excellent metabolic stability across species.
The D3 receptor selective antagonists/partial agonists can dose-dependently inhibit oxycodone self-administration, reduce oxycodone-seeking behavior, and lower the motivation for oxycodone intake.
These compounds do not compromise opioid analgesia and can potentiate antinociceptive effects of opioid analgesics at subtherapeutic doses, enabling lower opioid dosing and reducing dose escalation.
They reduce naloxone-precipitated conditioned place aversion in opioid-dependent animals, suggesting mitigation of withdrawal symptoms.
They can enhance the effectiveness of Medication Assisted Treatment regimens for opioid use disorders.
Documented Applications
Treating pain in patients by combined administration of opioid analgesics and selective dopamine D3 receptor antagonist/partial agonists to reduce opioid dose escalation and dependence development.
Treating opioid use disorders by administering selective dopamine D3 receptor antagonist/partial agonists with Medication Assisted Treatment agents to mitigate opioid addiction, reduce withdrawal severity, and prevent relapse.
Use of selective dopamine D3 receptor antagonist/partial agonists in combination with opioid analgesics to enhance analgesic efficacy and reduce opioid abuse liability.
Potential clinical use in post-operative pain management to reduce development of opioid dependence while maintaining analgesia.
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