Mu opioid receptor agonist analogs of the endomorphins

Inactive Publication Date: 2016-06-23
TULANE EDUCATIONAL FUND +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0024]Six critical side effects of currently used opioids were surprisingly reduced or absent with the compounds of Formula I: abuse liability, respiratory depression, motor impairment, tolerance, hyperalgesia, and glial activation. This extensive profile of low side effects for peptides shown to cross the blood brain barrier and provide prolonged antinociception is unprecedented. The lack of respiratory depression and motor impairment provides an improved safety profile. The lack of glial activation by a mu agonist, where morphine induces a proinflammatory response, is a novel finding that suggests both a mechanism for the reduce

Problems solved by technology

Opioids, and morphine in particular, induce proinflammatory glial cell, CGRP, or P2X7 receptor activation, which leads

Method used

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  • Mu opioid receptor agonist analogs of the endomorphins
  • Mu opioid receptor agonist analogs of the endomorphins
  • Mu opioid receptor agonist analogs of the endomorphins

Examples

Experimental program
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Example

Example 1

Binding and Activation of Human Opioid Receptors

[0073]The peptides of Formula I showed surprisingly high affinity (subnanomolar) for the human mu opioid receptor with selective binding relative to the delta and kappa opioid receptors. The compounds were tested in standard binding assays using 3H-DAMGO (tritiated [D-Ala2, N-Me-Phe4, Gly-ol]-enkephalin; CAS #78123-71-4), 3H-DPDPE (CAS#88373-73-3), and 3H-U69593 (CAS#96744-75-1) to label mu, delta and kappa receptors, respectively, in membranes from CHO cells expressing human cloned receptors. As shown in Table 2, endomorphin-1 (EMI, SEQ ID NO:8) and endomorphin-2 (EM2, SEQ ID NO:9) are the most selective endogenous mu agonists previously reported. Analogs based on these natural opioids show greater affinity for the mu receptor, albeit with less selectivity. Tetrapeptide endomorphin analogs described earlier (U.S. Pat. No. 5,885,958; ck1, Tyr-c[D-Lys-Trp-Phe] (SEQ ID NO:10); ck2, Tyr-c[D-Lys-Phe-Phe] (SEQ ID NO:11)) are also s...

Example

Example 2

Providing Analgesia of Greater Duration, but with Reduced Respiratory Depression, Relative to Morphine after Intravenous Administration

[0079]Respiratory depression is a major safety issue in the use of opioids. An opioid providing analgesia as effective as that produced by morphine, but with less respiratory depression, would be a major advance for the safe use of opioid analgesics. Effectiveness after systemic administration, such as intravenous (i.v.) injection, is unusual for peptide-based compounds, and would be critical for the clinical utility thereof. Two peptides (Compounds 1 and 2) were tested for their effects on respiration (minute ventilation) and duration of antinociception relative to morphine. Rats with indwelling jugular catheters were placed in a BUXCO whole body plethysmograph apparatus for determining multiple respiratory parameters. For 20 minutes following i.v. injection of vehicle (saline), baseline minute ventilation was determined. Animals were then ...

Example

Example 3

Providing Analgesia of Greater Duration than Morphine with Reduced Impairment of Neuromotor Coordination and Cognitive Function

[0081]Neuromotor and cognitive impairment are characteristics of opioids that are of particular importance in two populations, i.e., military combat troops, where escape from immediate danger can require unimpaired motor and cognitive skills, and the elderly, where these impairments can exacerbate compromised function including impaired balance, which can lead to increased risk of fractures.

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Abstract

The invention relates to cyclic peptide agonists that bind to the mu (morphine) opioid receptor and their use in the treatment of acute and/or chronic pain. Embodiments of the invention are directed to cyclic pentapeptide and hexapeptide analogs of endomorphin that have (i) a carboxy-terminal extension with an amidated amino acid and (ii) a D-amino acid substitution in position 2. These peptide analogs exhibit decreased tolerance relative to morphine, increased solubility compared to similar tetrapeptide analogs, while maintaining favorable or improved therapeutic ratios of analgesia to side effects.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation-in-part of U.S. application Ser. No. 14 / 268,057, filed on May 2, 2014, which is a continuation of U.S. application Ser. No. 13 / 477,423, filed on May 22, 2012, now U.S. Pat. No. 8,716,436, which is a continuation-in-part of PCT / US2011 / 43306, filed on Jul. 8, 2011, which claims the benefit of U.S. Provisional Application Ser. No. 61 / 363,039, filed on Jul. 9, 2010, each of which is incorporated herein by reference in its entirety.STATEMENT OF GOVERNMENT SUPPORT[0002]A portion of the work described herein was supported by a Senior Career Research and Merit Award, Grant No. I01BX001489 from the Department of Veteran Affairs, Grant No. DM090595 from the Department of Defense, and Grant No. N00014-09-is 1-0648 from the Office of Naval Research of the Department of Defense. The United States government has certain rights in this invention.INCORPORATION OF SEQUENCE LISTING[0003]The biological sequence information...

Claims

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Application Information

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IPC IPC(8): C07K7/64
CPCA61K38/00C07K7/64C07K7/56C07K14/665C07K7/06G01N33/9486G01N2333/70571G01N2333/726G01N2500/04
Inventor ZADINA, JAMES E.HACKLER, LASZLO
Owner TULANE EDUCATIONAL FUND
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