# Pharmacological Probes based on mitragynine pseudoindoxyl

> **NIH NIH R33** · ST. LOUIS COLLEGE OF PHARMACY · 2021 · $395,106

## Abstract

Program Summary
The ideal pain medication would be devoid of the serious side effects associated with the
currently used opioids (respiratory depression, constipation, dependence, addiction).
Mitragynine is a corynanthe-type indole alkaloid isolated as the major alkaloid component of the
leaves of the plant Mitragyna speciosa; a “legal high” sold over the internet as kratom, and is
currently unregulated. Mitragynine-related natural products possess affinity for mu opioid
receptors and exhibit analgesia in rodent models when given systemically. Mitragynine
pseudoindoxyl (MP), is a semi-synthetic analog related to mitragynine, which is more potent of
an analgesic compared to mitragynine. This scaffold also behaves as delta antagonist, and as
a biased mu agonist towards G-protein transduction systems. MP shows reduced respiratory
depression, tolerance and dependence, and no rewarding behavior in mice. Thus, this template
represents an excellent starting point for developing analgesics with a superior side effect profile
to all clinically used mu opioid analgesics. We will also to create a library of derivatives of MP by
using total and semi-synthetic approaches. Detailed pharmacological characterization of these
analogs will lead to a substantially better understanding of SAR of MP-type compounds. Our
final goal is to characterize the compounds pharmacologically in vitro and in vivo. Analogs will
be evaluated for potency and an advantageous side-effect profile (i.e. absent or reduced
tolerance, dependence, respiratory depression, constipation, reward and aversion).
Physicochemical properties like solubility, stability, permeation and CNS penetration, also will
be studied. The long-term objective of this proposal is to understand if G-biased MOR agonism
in combination with DOR antagonism can lead to reduced tolerance/physical dependence in
multiple rodent pain models (thermal, inflammatory, neuropathic) and also lead to synthesis of
non-addicting and non-abusable analgesics. The central hypothesis is to diversify the MP
template using our total synthetic/semi-synthetic approaches and prepare compounds with a
MOR-DOR mixed agonist-antagonist profile with increased metabolic stability. These goals will
be accomplished through an interdisciplinary team with significant experience in medicinal
chemistry, synthetic chemistry, pharmacology, neuroscience, drug metabolism and
pharmacokinetics.

## Key facts

- **NIH application ID:** 10236559
- **Project number:** 5R33DA045884-04
- **Recipient organization:** ST. LOUIS COLLEGE OF PHARMACY
- **Principal Investigator:** Susruta Majumdar
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,106
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236559

## Citation

> US National Institutes of Health, RePORTER application 10236559, Pharmacological Probes based on mitragynine pseudoindoxyl (5R33DA045884-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10236559. Licensed CC0.

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