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-11337971-B2
Publication Date
2022-05-24
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 relates to novel methods of treating pain and opioid use disorders by using selective dopamine D3 receptor antagonists/partial agonists in combination with opioid analgesics or Medication Assisted Treatment (MAT) agents. The disclosed compounds, especially those defined by Formula (I) or (II), when used with opioids, can mitigate the development of opioid dependence by preventing dose escalation, maintaining analgesic effects, or enabling analgesia with lower opioid doses. These compounds can also augment the effectiveness of current MAT regimens like methadone or buprenorphine for opioid use disorder treatment.
Prescription opioids, while effective analgesics, carry risks of tolerance, dependence, and abuse, contributing significantly to public health and economic burdens. Current MAT options, although improving abstinence, have limitations including side effects and inadequate effectiveness in some patients. Dopamine D3 receptors have been implicated as targets for substance use disorder treatment due to their role in reward and addiction-related behaviors. There is a need for safer pain management approaches that reduce opioid dependence risk and enhance MAT efficacy.
The invention provides methods and pharmaceutical compositions comprising selective dopamine D3 receptor antagonist/partial agonist compounds combined with opioid analgesics or MAT agents to treat pain, mitigate opioid addiction development, reduce withdrawal symptoms, and prevent relapse. The compounds of Formula (I) and (II) exhibit high affinity and selectivity for D3 receptors with improved metabolic stability, enabling lower dosing and reducing side effect potential. Animal studies demonstrate that these compounds inhibit oxycodone self-administration, drug-seeking behavior, and alleviate withdrawal symptoms without compromising opioid analgesia, supporting their potential clinical utility.
Claims Coverage
The claims encompass methods of treating opioid use disorders, mitigating addiction development, reducing withdrawal severity, preventing relapse, and treating pain by administering selective dopamine D3 receptor antagonist/partial agonists of Formula (II) in combination with Medication Assisted Treatment agents or opioid analgesics. The coverage includes pharmaceutical compositions and kits containing these compounds and therapeutic agents.
Method of treating opioid use disorders with selective D3 receptor antagonists and Medication Assisted Treatment agents
A method providing a therapeutically effective amount of a Medication Assisted Treatment agent that is an opioid agonist or partial agonist, along with a therapeutically effective amount of a selective dopamine D3 receptor antagonist/partial agonist compound of Formula (II), a stereoisomer, or salt, to a patient in need for treating opioid use disorders, preventing addiction development, mitigating withdrawal symptoms, or preventing relapse.
Structural characteristics of the selective dopamine D3 receptor antagonists used in treatment
Selection of compounds of Formula (II) with specific substituents such as R10 as C2 alkyl and Ar groups including benzofuranyl, benzothienyl, imidazolyl and related heteroaryl groups optionally substituted with C1-C6 alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, carboxyl, amino, nitro, alkanoyl or halogen; with additional provisos on m, n, R14, R15, and bond types to define the compound's structure used in treatment.
Dosing regimens involving the selective dopamine D3 receptor antagonist and Medication Assisted Treatment agent
Methods comprising administering the compound of Formula (II) and Medication Assisted Treatment agent at least once daily for durations including one or more weeks, starting prior to opioid analgesic therapy initiation, continuing during opioid analgesic administration, and optionally for days after opioid discontinuation to provide therapeutic effects.
Pharmaceutical compositions and kits comprising the selective dopamine D3 receptor antagonist and therapeutic agents
Pharmaceutical compositions formulated as single or separate dosage forms containing the compound of Formula (II) and Medication Assisted Treatment agent and optionally opioid analgesics, with pharmaceutically acceptable carriers, suitable for oral, topical, or parenteral administration including controlled-release formulations. Kits comprising such compositions and instructions for use.
Methods of treating pain with opioid analgesics combined with selective D3 receptor antagonist compounds
Methods providing therapeutically effective amounts of an opioid analgesic or pharmaceutically acceptable salt and a compound of Formula (II), stereoisomer, or pharmaceutically acceptable salt, optionally along with Medication Assisted Treatment agents, to treat various types of pain while mitigating opioid dependence development.
The patent claims cover the use of selective dopamine D3 receptor antagonist/partial agonist compounds of Formula (II) in combination with Medication Assisted Treatment agents or opioid analgesics to treat opioid use disorders and pain. Features include specific structural embodiments of the compounds, dosing regimens covering pre-treatment and continuation during opioid therapy, and pharmaceutical compositions or kits suitable for various administration routes. These claims protect methods and compositions aimed at reducing opioid addiction risks while maintaining analgesic efficacy.
Stated Advantages
Selective dopamine D3 receptor antagonist/partial agonists prevent the development of opioid dependence by reducing the need for dose escalation while maintaining opioid analgesic effects or allowing lower opioid doses.
These compounds augment the effectiveness of current Medication Assisted Treatment regimens for opioid use disorders.
Compounds exhibit high selectivity and metabolic stability, enabling use at lower doses and reducing side effects.
They reduce oxycodone self-administration and drug-seeking behaviors without affecting general motor function or sucrose self-administration, suggesting specificity for opioid reinforcement.
They do not compromise opioid analgesia and can potentiate analgesic effects of subtherapeutic opioid doses.
Compounds attenuate naloxone-precipitated withdrawal symptoms and conditioned place aversion, reducing aversive effects associated with opioid withdrawal.
Documented Applications
Treatment of pain in patients by administering therapeutically effective amounts of selective dopamine D3 receptor antagonists/partial agonists with opioid analgesics to reduce opioid dose escalation and prevent dependence.
Treatment of opioid use disorders, including mitigating addiction development, reducing severity of withdrawal symptoms, and preventing relapse by co-administration of dopamine D3 receptor antagonist/partial agonists with Medication Assisted Treatment agents (e.g., methadone, buprenorphine).
Use of selective dopamine D3 receptor antagonist/partial agonist compounds to enhance the efficacy of current Medication Assisted Treatment regimens in opioid use disorder therapy.
Pharmaceutical compositions and kits combining opioid analgesics, Medication Assisted Treatment agents, and selective dopamine D3 receptor antagonist/partial agonists for improved pain management and opioid addiction treatment.
Potential treatment of substance use disorders including stimulants, cannabis, alcohol, nicotine, schizophrenia and related mental disorders, cognitive disorders, impulsivity, obesity, depression, bipolar disorder, and dyskinesias associated with Parkinson's disease or L-DOPA treatment using the selective dopamine D3 receptor antagonists.
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