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Deuterated mitragynine analogs as safer opioid modulators in the mitragynine class

A technology of pharmacy, composition, applied in the field of deuterated mitragynine analogs as safer opioid modulators in mitragynines, capable of solving problems such as loss, negative medicine and social cognition

Pending Publication Date: 2022-02-11
THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, with the advent of tricyclic antidepressants (TCAs) in the 1950s, the psychiatric use of opioids quickly fell out of favor, and due to the negative medical and social perceptions that their potential for abuse could lead to, most of their dormant

Method used

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  • Deuterated mitragynine analogs as safer opioid modulators in the mitragynine class
  • Deuterated mitragynine analogs as safer opioid modulators in the mitragynine class
  • Deuterated mitragynine analogs as safer opioid modulators in the mitragynine class

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0654] Example 1: Effect of 3-dehydromitragynine in the rotarod test in mice

[0655] The rotarod test is useful for measuring motor coordination in rodents, and thus for identifying test drugs that induce ataxic effects. 3-Dehydromitragynine (DHM) reduced the performance of mice in this test in a dose-dependent manner, suggesting that this compound impairs motor coordination ( figure 1 ).

[0656] Animals: 7-week-old male C57BL / 6J mice (n=10 / treatment) purchased from The Jackson Laboratory (Bar Harbor, ME) were used for this study. Animals were housed in groups of five and acclimatized for 1 week prior to testing. Mice had access to food and water ad libitum and were maintained on a 12 hour light / dark cycle. All tests were performed in a light cycle.

[0657] Drug: DHM hydrochloride dissolved in double distilled H containing 10% N-methyl-2-pyrrolidone (NMP) 2 O middle. Drug or vehicle was administered subcutaneously in a volume of 10 mL / kg body weight 15 minutes befor...

example 2

[0659] Example 2: Lethality of 3-dehydromitragynine in mice

[0660] Treatment of mice with 3-dehydromitragynine (DHM) resulted in death in a dose-dependent manner in two different strains, demonstrating the general toxicity of this metabolite (Figure 2).

[0661] Lethality assay: Groups of mice (n=6 per dose, 129Sv6 or CD-1 strain) were treated subcutaneously (s.c.) with different doses of DHM, and lethality was tested 24 hours after drug administration.

example 3

[0662] Example 3: Attenuated Formation of 3-Dehydromitragynine in Liver Microsomes

[0663] In human liver microsomes (HLM), both 7-hydroxymitragynine (7-OH) and 3-dehydromitragynine (DHM) are formed as metabolites of mitragynine (Figure 3) . For example, the deuteration of the 3-position of mitragynine in 3-deutero-mitragynine (3-DM) weakens the formation of DHM by kinetic isotope effect ( Figure 3A ), without affecting the oxidative metabolism at position 7 to give 3-deutero-7-hydroxymitragynine (3-d-7-OH, similar to 7-OH formed from mitragynine) ( Figure 3B ). Thus, 3-DM offers a significant advantage over mitragynine in that it attenuates the formation of the toxic metabolite DHM while having no effect on the formation of the active metabolite 3-d-7-OH.

[0664] HLM metabolite formation: Pooled HLMs from 50 adult male and female donors (XenoTech H0630, lot 1610016) were used. Microsomal incubations with mitragynine and 3-DM were performed in 5 aliquots of 40 μL eac...

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Abstract

The present invention provides a compound having the structure: or a pharmaceutically acceptable salt or ester thereof, and methods of using the compound to treat pain, depressive disorders, mood disorders, anxiety disorders, opioid use disorder, and opioid withdrawal symptoms.

Description

[0001] This application claims priority to U.S. Provisional Application No. 62 / 800,369, filed February 1, 2019, the contents of which are hereby incorporated by reference. [0002] Throughout this application, certain publications are referenced within parentheses. Full citations for these publications can be found immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. Background technique [0003] Opioid receptors, and specifically the μ-opioid receptor (MOR) are one of the longest and best studied molecular signaling systems in the central nervous system (Pasternak, G.W. et al. 2013). Likewise, the prototypical small-molecule agonist of these receptors, morphine, has been used by humans since ancient times as an important analgesic and recreational euphoric agent. Indeed, MOR agonists, encompa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/438C07D471/14
CPCC07D471/14A61K45/06A61K31/4375A61K31/55A61P25/24A61P25/22A61P25/36A61K31/485A61K2300/00A61P25/00
Inventor 安德鲁·C·克鲁格尔达里波尔·塞姆斯乔纳森·A·贾维奇苏斯鲁塔·马宗达
Owner THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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